Tetrahydroquinoline analogues as muscarinic agonists

ABSTRACT

The present invention relates to tetrahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

RELATED APPLICATIONS

The present application is a continuation-in-part of application Ser.No. 10/329,455, filed Dec. 23, 2002, which in turn claims priority toU.S. Provisional Application Ser. No. 60/344,722, filed Dec. 28, 2001,both of which is incorporated by reference herein in its entirety,including any drawings.

FIELD OF THE INVENTION

The present invention relates to compounds that affect cholinergicreceptors, especially muscarinic receptors. The present inventionprovides compounds that are agonists of cholinergic receptors includingmuscarinic receptors, especially the M₁ and M₄ subtype of muscarinicreceptors. The invention also provides methods of using the providedcompounds for modulating conditions associated with cholinergicreceptors, especially for treating or alleviating disease conditionsassociated with muscarinic receptors, such as the M₁ and/or M₄ receptorsubtypes.

BACKGROUND

Muscarinic cholinergic receptors mediate the actions of theneurotransmitter acetylcholine in the central and peripheral nervoussystems. Muscarinic receptors play a critical role in the centralnervous system mediating higher cognitive functions, as well as in theperipheral parasympathetic nervous system where they mediate cardiac,respiratory, digestive, and endocrine and exocrine responses. Fivedistinct muscarinic receptor subtypes have been identified, M₁-M₅. Themuscarinic M₁ receptor subtype is predominantly expressed in thecerebral cortex and is believed to be involved in the control of highercognitive functions; the M₂ receptor is the predominant subtype found inheart and is involved in the control of heart rate; the M₃ receptor iswidely expressed in many peripheral tissues and is believed to beinvolved in gastrointestinal and urinary tract stimulation as well assweating and salivation; the M₄ receptor is present in brain and may beinvolved in locomotion; the M₅, receptor is present in the brain whereits role is at present poorly defined. M₁ and M₄ have been particularlyassociated with the dopaminergic system.

Conditions associated with cognitive impairment, such as Alzheimer'sdisease, are accompanied by a reduction of acetylcholine content in thebrain. This is believed to be the result of degeneration of cholinergicneurons of the basal forebrain, which widely innervate multiple areas ofthe brain, including the association cortices and hippocampus, that arecritically involved in higher processes.

Efforts to increase acetylcholine levels have focused on increasinglevels of choline, the precursor for acetylcholine synthesis, and onblocking acetylcholineesterase (AChE), the enzyme that metabolizesacetylcholine. Attempts to augment central cholinergic function throughthe administration of choline or phosphatidylcholine have not beensuccessful. AChE inhibitors have shown therapeutic efficacy, but havebeen found to have frequent cholinergic side effects due to peripheralacetylcholine stimulation, including abdominal cramps, nausea, vomiting,and diarrhoea. These gastrointestinal side effects have been observed inabout a third of the patients treated. In addition, some AChEinhibitors, such as tacrine, have also been found to cause significanthepatotoxicity with elevated liver transaminases observed in about 30%of patients. The adverse effects of AChE inhibitors have severelylimited their clinical utility.

The dopamine hypothesis of schizophrenia suggests that increaseddopamine neurotransmission underlies the positive symptoms of thedisease and is supported by the evidence that dopamine receptor blockadeis effective in ameliorating such psychotic symptoms. Further, drugsthat enhance dopamine neurotransmission in the brain causepsychotic-like episodes in man and exacerbate psychotic symptoms inschizophrenic patients. In animal studies, drugs that increase dopamineneurotransmission cause behavioural effects such as increasedlocomotion, climbing and deficits in prepulse inhibition. Knownantipsychotics and dopamine receptor antagonists can block thesebehavioural effects. Unfortunately, dopamine receptor antagonists alsocause severe extrapyramidal side effects in patients as predicted byinduction of catalepsy in animal models. These extrapyramidal sideeffects include tremor, bradykinesia, akithesias, and tardivedyskinesias.

Due in part to these observations, the discovery of agents with M₁receptor agonist activity has been sought after for the treatment ofdementia. However, existing agents lack specificity in their actions atthe various muscarinic receptor subtypes. Known M₁ muscarinic agonistssuch as arecoline have also been found to be weak agonists of M₂ as wellas M₃ receptor subtypes and are ineffective in the treatment ofcognitive impairment, due in large part to their dose-limiting M₂ and M₃receptor mediated side effects.

Xanomeline (Shannon et al., J. Pharmacol. Exp. Ther. 1994, 269, 271;Shannon et al., Schizophrenia Res. 2000, 42, 249) is an M₁/M₄ preferringmuscarinic receptor agonist with little or no affinity for dopaminereceptors despite inhibiting A10 but not A9 dopamine cells. Thethiadiazole derivative PTAC has been reported (Shannon et al., EuropeanJournal of Pharmacology, 1998, 356, 109) to have partial agonist effectat muscarinic M₂ and M₄ receptors and antagonist effect at muscarinicM₁, M₃, and M₅ receptors as well as exhibiting functional dopamineantagonism.

Recently, muscarinic agonists including xanomeline have been shown to beactive in animal models with similar profiles to known antipsychoticdrugs, but without causing catalepsy (Bymaster et al., Eur. J.Pharmacol. 1998, 356, 109, Bymaster et al., Life Sci. 1999, 64, 527,Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901, Shannon et al.,Schizophrenia Res. 2000, 42, 249). Further, xanomeline was shown toreduce psychotic behavioural symptoms such as delusions, suspiciousness,vocal outbursts, and hallucinations in Alzheimer's disease patients(Bodick et al., Arch. Neurol. 1997, 54, 465), however treatment inducedside effects that severely limit the clinical utility of this compound.

Analogues of 1,2,5-thiadiazole have been reported (Sauerberg et al., J.Med Chem. 1998, 41, 4378) to have high affinity and selectivity forcentral muscarinic receptors as well as exhibiting functional dopamineantagonism despite lack of affinity for dopamine receptors.

The present investigators have, in part, focussed their efforts on thedevelopment of molecules that simultaneously reduced the positivesymptoms and improved the negative symptoms and the cognitiveimpairments associated with schizophrenia as a novel treatment of mentaldisorders. It is the intent of the present investigators to demonstratethat muscarinic M₁ and/or M₄ agonists with combined D₂ antagonistactivity may possess superior antipsychotic efficacy without the sideeffects associated with high dose D₂ antagonism alone. The D₂ antagonistproperties of some of the compounds of the present invention maycontribute to a reduction in the positive symptoms of this disease.

Based on distribution of M₁ and M₄ receptors in the cerebral cortex andhippocampus (the areas involved in higher order cognitive functions),the M₁ and/or M₄ agonist properties of these compounds may reduce thecognitive dulling and perhaps ameliorate other negative symptomsassociated with schizophrenia. (Friedman, Biol. Psychiatry, 1999, 45, 1;Rowley, J. Med. Chem. 2001, 44, 477; Felder, J. Med. Chem. 2000, 43,4333). This unique combination of central nervous system activities inone molecule is unprecedented and may lead to the development of anentirely new class of antipsychotic drugs, ones with the superiorclinical properties without the limiting side-effect profile.

U.S. Pat. No. 3,324,137 and U.S. Pat. No. 3,365,457 describeN-[indolyl-lower-alkanoyl]-1,5-iminocycloalkanes and iminocycloalkanesnot encompassed by the invention.

EP 0 584 487 describes 4,5-dihydo-4-oxo-pyrroles with linked topiperazine rings not encompassed by the invention.

Mokrosz et al (Pharmazie, 52, 1997, 6, p 423) describesN[3-(4-aryl)-1-piperazinyl)propyl] derivatives of indolin-2(1H)-one,quinolin-2-(1H)-one and isoquinolin-1-(2H)-one, which are notencompassed by the invention.

SUMMARY OF THE INVENTION

The invention provides novel compounds of formula I, as well as saltsand isomers thereof

-   -   wherein R¹ is a monoradical selected from the group consisting        of optionally substituted C₁₋₆-alkyl, optionally substituted        C₂₋₆-alkylidene, optionally substituted C₂₋₆-alkenyl, optionally        substituted C₂₋₆-alkynyl, optionally substituted O—C₁₋₆-alkyl,        optionally substituted O—C₂₋₆-alkenyl, optionally substituted        O—C₂₋₆-alkynyl; optionally substituted S—C₁₋₆-alkyl, optionally        substituted S—C₂₋₆-alkenyl, optionally substituted        S—C₂₋₆-alkynyl;    -   m is 0, 1 or 2;    -   C₃-C₄ is CH₂—CH or CH═C or C₄ is CH and C₃ is absent;    -   R² and R³ are independently selected from the group consisting        of hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted O—C₁₋₆ alkyl, halogen, hydroxy or selected such that        R² and R³ together form a ring system;    -   each R⁴ and R⁵ is independently selected from the group        consisting of hydrogen, halogen, hydroxy, optionally substituted        C₁₋₆-alkyl, optionally substituted O—C₁₋₆alkyl, optionally        substituted aryl-C₁₋₆ alkyl, and optionally substituted        arylheteroalkyl;    -   L¹ and L² are biradicals independently selected from the group        consisting of —C(R⁶)═C(R⁷), —C(R⁶)═N—, —N═C(R⁶)—, —S—, —NH— and        —O—; wherein only one of L¹ and L² may be selected from the        group consisting of —S—, —NH— and —O—;    -   Y is selected from the group consisting of O, S, and H₂;    -   X is a biradical selected from the group consisting of        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—,        C(R⁶)(R⁷)—O—, —S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—,        —N(R^(N))—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—N(R^(N))—,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,        —O—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,S—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,        N(R^(N))—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—O,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—S, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—N(R^(N))—,        —C(R⁶)(R⁷)—C(R⁶)═C(R⁷)—, and —C(R⁶)═C(R⁷)—C(R⁶)(R⁷), wherein R⁶        and R⁷ are independently selected from the group consisting of        hydrogen, halogen, hydroxy, nitro, cyano, NR^(N)R^(N),        N(R^(N))—C(O) N(R^(N)), optionally substituted C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, , optionally substituted        O—C₁₋₆-alkyl, optionally substituted O-aryl, optionally        substituted O—C₂₋₆-alkenyl, optionally substituted        O—C₂₋₆-alkynyl    -   wherein R^(N) is selected from the group consisting of hydrogen,        and optionally substituted C₁₋₆-alkyl.

The invention further provides compositions comprising

-   -   i) one or more compounds of formula I, and;    -   ii) at least one pharmaceutically acceptable excipient or        carrier.

The invention also provides methods of treating a disease in a mammal,such as a human, wherein modulation of the activity of a cholinergicreceptor is associated with a physiologically beneficial response insaid disease of said mammal. In one embodiment, a method includesadministering an effective amount of a compound of formula I.

Thus, the invention provides methods of treating or preventing oralleviating one or more symptoms associated with a disorder in a mammal,such as a human, said disorder associated with a muscarinic receptor,for example, the M₁ muscarinic receptor subtype. In one embodiment, amethod includes the administration of an effective amount of thecompound of formula I, a pharmaceutically acceptable salt thereof, astereoisomer thereof, or a pharmaceutical composition comprising eitherentity. Particular disorders treatable by a method of the inventioninclude, for example, Alzheimer's disease, Parkinson's disease,schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de laTourette's Syndrome, Down Syndrome, Pick disease, dementia, clinicaldepression, age-related cognitive decline, cognitive impairment,forgetfulness, confusion, memory loss, attentional deficits, deficits invisual perception, depression, pain, sleep disorders, psychosis, suddeninfant death syndrome, increased intraocular pressure and glaucoma.

The invention additionally provides a method of treating a mentaldisorder wherein the physiologically beneficial response is due tomodulation in terms of M₁ agonism; M₁ and M₄ agonism; both M₁ agonismand D₂ antagonism; or M₁ and M₄ agonism and D₂ antagonism.

The invention additionally provides the use of a compound of formula I,a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or apharmaceutical composition comprising either entity, for the preparationof a medicament for the treatment of diseases or disorders associatedwith a cholinergic receptor or ligand thereof.

The invention therefore provides methods for the preparation of amedicament for the treatment of diseases or disorders selected from thegroup consisting of Alzheimer's disease, Parkinson's disease,schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de laTourette's Syndrome, Down Syndrome, Pick disease, dementia, clinicaldepression, age-related cognitive decline, cognitive impairment,forgetfulness, confusion, memory loss, attentional deficits, deficits invisual perception, depression, pain, sleep disorders, psychosis, suddeninfant death syndrome, increased intraocular pressure and glaucoma.

The invention further provides methods of increasing an activity of acholinergic receptor. In one embodiment, a method includes contactingthe cholinergic receptor or a system containing the cholinergic receptorwith an effective amount of at least one compound of formula I toincrease an activity of the cholinergic receptor.

The invention provides kits including one or more compounds of theinvention, and instructions for practicing a method of the invention. Inone embodiment, instructions are for treating or preventing oralleviating one or more symptoms associated with a disorder in a mammal,such as a human, said disorder associated with a muscarinic receptor,for example, the M₁ muscarinic receptor subtype. In another embodiment,instructions are for increasing cholinergic receptor activity oractivating cholinergic receptors.

DESCRIPTION OF THE INVENTION

For the purpose of the current disclosure, the following definitionsshall in their entireties be used to define technical terms.

The term “agonist” is defined as a compound that increases the activityof a receptor when it contacts the receptor.

The term “antagonist” is defined as a compound that competes with anagonist or inverse agonist for binding to a receptor, thereby inhibitingor blocking the action of an agonist or inverse agonist on the receptor.However, an antagonist (also known as a “neutral” antagonist) has noeffect on constitutive receptor activity.

The term “inverse agonist” is defined as a compound that decreases thebasal activity of a receptor (i.e., signaling mediated by the receptor).Such compounds are also known as negative antagonists. An inverseagonist is a ligand for a receptor that causes the receptor to adopt aninactive state relative to a basal state occurring in the absence of anyligand. Thus, while an antagonist can inhibit the activity of anagonist, an inverse agonist is a ligand that can alter the conformationof the receptor in the absence of an agonist. The concept of an inverseagonist has been explored by Bond et al. in Nature 374:272 (1995). Morespecifically, Bond et al. have proposed that unliganded β₂-adrenoceptorexists in an equilibrium between an inactive conformation and aspontaneously active conformation. Agonists are proposed to stabilizethe receptor in an active conformation. Conversely, inverse agonists arebelieved to stabilize an inactive receptor conformation. Thus, while anantagonist manifests its activity by virtue of inhibiting an agonist, aninverse agonist can additionally manifest its activity in the absence ofan agonist by inhibiting the spontaneous conversion of an unligandedreceptor to an active conformation.

The “M₁-receptor” is defined as a receptor having an activitycorresponding to the activity of the ml muscarinic receptor subtypecharacterized through molecular cloning and pharmacology.

The term “subject” refers to an animal, for example a mammal, such as ahuman, who is the object of treatment, observation or experiment.

The term “selective” is defined as a property of a compound whereby anamount of the compound sufficient to effect a desired response from aparticular receptor type, subtype, class or subclass causes asubstantially smaller or no effect upon the activity of other receptortypes.

The EC₅₀ for an agonist is intended to denote the concentration of acompound needed to achieve 50% of a maximal response seen in an in vitroassay such as R-SAT. For inverse agonists, EC50 is intended to denotethe concentration of a compound needed to achieve 50% inhibition of anR-SAT response from basal, no compound, levels.

As used herein, the term “coadministration” of pharmacologically activecompounds refers to the delivery of two or more separate chemicalentities, whether in vitro or in vivo. Coadministration refers to thesimultaneous delivery of separate agents; to the simultaneous deliveryof a mixture of agents; as well as to the delivery of one agent followedby delivery of a second agent or additional agents. In all cases, agentsthat are coadministered are intended to work in conjunction with eachother.

In the present context, the term “C₁₋₆-alkyl” means a linear or branchedsaturated hydrocarbon chain wherein the longest chain has from one tosix carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, andhexyl.

In the present context, the term “C₂₋₈-alkenyl” means a linear orbranched hydrocarbon group having from two to eight carbon atoms andcontaining one or more double bonds. Illustrative examples ofC₂₋₈-alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl,pentenyl, hexenyl, heptenyl and octenyl. Illustrative examples ofC₂₋₈-alkenyl groups with more than one double bond include butadienyl,pentadienyl, hexadienyl, heptadienyl, heptatrienyl and octatrienylgroups as well as branched forms of these. The position of theunsaturation (the double bond) may be at any position along the carbonchain.

In the present context the term “C₂₋₈-alkynyl” means a linear orbranched hydrocarbon group containing from two to eight carbon atoms andcontaining one or more triple bonds. Illustrative examples ofC₂₋₈-alkynyl groups include ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl and octynyl groups as well as branched forms of these.The position of unsaturation (the triple bond) may be at any positionalong the carbon chain. More than one bond may be unsaturated such thatthe “C₂₋₈-alkynyl” is a di-yne or enedi-yne as is known to the personskilled in the art.

In the present context, the term “C₃₋₈-cycloalkyl” includes three-,four-, five-, six-, seven-, and eight-membered rings comprising carbonatoms only, whereas the term “heterocyclyl” means three-, four-, five-,six-seven-, and eight-membered rings wherein carbon atoms together withfrom 1 to 3 heteroatoms constitute said ring. The heteroatoms of suchheterocyclyl groups are independently selected from oxygen, sulphur, andnitrogen.

The term “Heterocyclyl” groups may further contain one or more carbonylor thiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides, cyclic carbamates, and the like.

C₃₋₈-cycloalkyl and heterocyclyl rings may optionally contain one ormore unsaturated bonds situated in such a way, however, that an aromaticπ-electron system does not arise.

Heterocyclyl rings may optionally also be fused to aryl rings, such thatthe definition includes bicyclic structures. Examples of such fusedheterocyclyl groups share one bond with an optionally substitutedbenzene ring. Examples of benzo-fused heterocyclyl groups include, butare not limited to, benzimidazolidinone, tetrahydroquinoline, andmethylenedioxybenzene ring structures.

Illustrative examples of “C₃₋₈-cycloalkyl” are the carbocyclescyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,cycloheptane, cycloheptene, 1,2-cycloheptadiene, 1,3-cycloheptadiene,1,4-cycloheptadiene and 1,3,5 cycloheptatriene.

Illustrative examples of “heterocyclyls” are the heterocyclestetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, thiazoline, thiazolidine, 1,3-oxathiolane,. Binding to theheterocycle may be at the position of a heteroatom or via a carbon atomof the heterocycle, or, for benzo-fused derivatives, via a carbon of thebenzenoid ring.

In the present context the term “aryl” means a carbocyclic aromatic ringor ring system. Moreover, the term “aryl” includes fused ring systemswherein at least two aryl rings, or at least one aryl and at least oneC₃₋₈-cycloalkyl share at least one chemical bond. Illustrative examplesof “aryl” rings include optionally substituted phenyl, naphthalenyl,phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.An example of an aryl group is phenyl. The term “aryl” relates toaromatic, typically benzenoid groups connected via one of thering-forming carbon atoms, and optionally carrying one or moresubstituents selected from halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. As stated, aryl groups maybe phenyl, and, most suitably, substituted phenyl groups, carrying oneor two, same or different, of the substituents listed above. One patternof substitution is para and/or meta. Representative examples of arylgroups include, but are not limited to, phenyl, 3-halophenyl,4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl,4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl,hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl,alkoxyphenyl.

In the present context the term “aryl(C₁₋₆-alkyl)” means a carbocyclicaromatic ring as defined above connected via a C₁₋₆-alkyl group.

The term arylheteroalkyl should be interpreted as an aryl group, asdefined above, connected, as a substituent, via a C₁₋₆-alkyl tetherwhich, additionally, contains, in the chain, at least one atom selectedfrom the group consisting of oxygen, sulfur, and nitrogen.

In the present context, the term “heteroaryl” means a heterocyclicaromatic group where one or more carbon atoms in an aromatic ring havebeen replaced with one or more heteroatoms selected from the groupcomprising nitrogen, sulphur, phosphorous and oxygen.

Furthermore, the term “heteroaryl” comprises fused ring systems whereinat least one aryl ring and at least one heteroaryl ring, at least twoheteroaryl rings, at least one heteroaryl ring and at least oneheterocyclyl ring, or at least one heteroaryl ring and at least oneC₃₋₈-cycloalkyl ring share at least one chemical bond.

The term “heteroaryl” is understood to relate to aromatic, C₂₋₆ cyclicgroups further containing one O or S atom or up to four N atoms, or acombination of one O or S atom with up to two N atoms, and theirsubstituted as well as benzo- and pyrido-fused derivatives, typicallyconnected via one of the ring-forming carbon atoms. Heteroaryl groupsmay carry one or more substituents, selected from halo, hydroxy, amino,cyano, nitro, alkylamido, acyl, C₁₋₆-alkoxy, C₁₋₆-alkyl,C₁₋₆-hydroxyalkyl, C₁₋₆-aminoalkyl, C₁₋₆-alkylamino, alkylsulfenyl,alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Particularheteroaryl groups are five- and six-membered aromatic heterocyclicsystems carrying 0, 1, or 2 substituents, which may be the same as ordifferent from one another, selected from the list above. Representativeexamples of heteroaryl groups include, but are not limited to,unsubstituted and mono- or di-substituted derivatives of furan,benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole,oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,isothiazole, imidazole, benzimidazole, pyrazole, indazole, andtetrazole, as well as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, triazole, benzotriazole, quionoline, isoquinoline,pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrrole,phenoxazole, oxazole, isoxazole, oxadiazole, benzopyrazole, indazole,quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. Themost typical substituents are halo, hydroxy, cyano, O—C₁₋₆-alkyl,C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, amino-C₁₋₆-alkyl.

When used herein, the term “O—C₁₋₆-alkyl” means C₁₋₆-alkyloxy, oralkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy and hexyloxy

The term “halogen” includes fluorine, chlorine, bromine and iodine.

When used herein, the term “optionally substituted” means that the groupin question may be substituted one or several times, such as 1 to 5times, 1 to 3 times, or 1 to 2 times, with one or more groups selectedfrom C₁₋₆-alkyl, C₁₋₆-alkoxy, oxo (which may be represented in thetautomeric enol form), carboxyl, amino, hydroxy (which when present inan enol system may be represented in the tautomeric keto form), nitro,alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C₁₋₆-alkoxycarbonyl,C₁₋₆-alkylcarbonyl, formyl, mono- and di(C₁₋₆-alkyl)amino; carbamoyl,mono- and di(C₁₋₆-alkyl)aminocarbonyl, amino-C₁₋₆-alkyl-aminocarbonyl,mono- and di(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl,C₁₋₆-alkylcarbonylamino, cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy,C₁₋₆-alkylsulphonyloxy, dihalogen-C₁₋₆-alkyl, trihalogen-C₁₋₆-alkyl, andhalo. In general, the above substituents may be susceptible to furtheroptional substitution

The term “salt” means pharmaceutically acceptable acid addition saltsobtainable by treating the base form of a functional group, such as anamine, with appropriate acids such as inorganic acids, for examplehydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric, orhydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and thelike; or organic acids, for example acetic, propionic, hydroacetic,2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanedioic,butanedioic, (Z)-2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydoxybenzoic,4-amino-2-hydroxybenzoic, and other acids known to the skilledpractitioner.

The method of the invention relates to the modulation of a cholinergicreceptor. Typically, said cholinergic receptor is a muscarinic receptor;one example of a cholinergic receptor is a muscarinic receptor ofM₁-receptor subtype. As can be seen from the Examples, in suitableembodiments, the cholinergic receptor may be either or both themuscarinic M₁-receptor and the muscarinic M₄-receptor subtypes. Thephysiologically beneficial response in the method of the invention istypically associated with the specific activation of the M₁-receptorsubtype over the M₂- or M₃-receptor subtype, or the specific activationof the M₁- and M₄-receptor subtypes over the M₂- or M₃-receptor subtype.Moreover, a physiologically beneficial response in a method of theinvention is typically associated with the agonistic activity of thecompound of formula I or IA. Thus, in one embodiment, the compound offormula I or IA is a muscarinic agonist, such as an M₁ agonist or an M₁and M₄ agonist.

A further aspect of the invention relates to a method of increasing theactivity of a cholinergic receptor. In one embodiment, a method includescontacting a cholinergic receptor or a system containing a cholinergicreceptor with an effective amount of at least one compound of formula Ior IA, as defined supra.

A related aspect of the invention is directed to a method of treating orpreventing or alleviating one or more symptoms associated with adisorder in a mammal, such as a human. In one embodiment, a methodincludes the administration of an effective amount of a compound offormula I or IA, said disorder associated with a muscarinic receptor,for example, M₁ muscarinic receptor subtype.

The disorders associated with the M₁ muscarinic receptor subtype aretypically mental disorders. Suitable mental disorders which can betreated by the method of the invention may be selected from the groupcomprising of cognitive impairment, forgetfulness, confusion, memoryloss, attentional deficits, deficits in visual perception, depression,pain, sleep disorders, psychosis, and increased intraocular pressure.

Disorders associated with the M₁ muscarinic receptor subtype need not bea mental disorder. For instance, increased intraocular pressure isassociated with the M₁ muscarinic receptor subtype. Disorders to whichthe method of the invention are directed therefore include non-mentaldisorders.

Disorders to which the method of the invention are directed may befurther selected from the group comprising neurodegenerative diseases,Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington'schorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, DownSyndrome, Pick disease, dementia, clinical depression, age-relatedcognitive decline, attention-deficit disorder, sudden infant deathsyndrome, and glaucoma.

As stated, the compounds of the invention have high selectivity andaffinity for the muscarinic M₁ receptor subtypes. As can be seen fromthe Examples, the compounds also have high affinity for one or both ofthe M₁ and M₄ receptor subtypes, selectively over other receptors suchas the M₂, M₃ and M₅ receptor subtypes. The compounds of the inventiontypically act, at least in part, as an M₁ agonist or as M₁ and M₄agonist.

The compounds of the invention also have an affinity for the dopamine D₂receptor. As discussed supra in connection with the dopamine hypothesisin relation to schizophrenia, compounds which act as both muscarinicagonists and dopamine antagonists may be keys to adequately treat manymental disorders. Thus, the invention is also directed to methods oftreating mental disorders, using compounds of the invention, saidcompounds acting as a D₂ antagonist or D₂ inverse agonist as well as amuscarinic agonist, particularly an M₁ agonist or as M₁ and M₄ agonist.Thus, the method of the invention may be such that the disease in amental disorder and the physiologically beneficial response to due tomodulation in terms of M₁ agonism; M₁ and M₄ agonism; both M₁ agonismand D₂ antagonism; or M₁ and M₄ agonism and D₂ antagonism.

In one aspect of the invention, the compounds of the invention areanti-psychotic agents, said anti-psychotic activity due to the compoundsof the invention acting as M₁ agonist; or as M₁ and M₄ agonists; oracting as an both M₁ agonists and D₂ antagonist; or as M₁ and M₄agonists and D₂ antagonists.

Another aspect of the invention relates to the use of a compound offormula IA, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising either entity, for the preparationof a medicament for the treatment of diseases or disorders associatedwith a cholinergic receptor or ligand thereof. The medicament may be forthe treatment of diseases associated with the receptors as discussedsupra and for disorders as discussed supra. A related aspect of theinvention is directed to a pharmaceutical composition comprising aneffective amount of a compound of formula I, as defined supra, orpharmaceutically acceptable salts thereof, a stereoisomer thereof, or apharmaceutical composition comprising either entity, together withpharmaceutically acceptable carriers or excipients.

The invention provides novel compounds of formula I, as well as saltsand isomers thereof

-   -   wherein R¹ is a monoradical selected from the group consisting        of optionally substituted C₁₋₆-alkyl, optionally substituted        C₂₋₆-alkylidene, optionally substituted C₂₋₆-alkenyl, optionally        substituted C₂₋₆-alkynyl, optionally substituted O—C₁₋₆-alkyl,        optionally substituted O—C₂₋₆-alkenyl, optionally substituted        O—C₂₋₆-alkynyl; optionally substituted S—C₁₋₆-alkyl, optionally        substituted S—C₂₋₆-alkenyl, optionally substituted        S—C₂₋₆-alkynyl;    -   m is 0, 1 or 2;    -   C₃-C₄ is CH₂—CH or CH═C or C₄ is CH and C₃ is absent;    -   R² and R³ are independently selected from the group consisting        of hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted O—C₁₋₆ alkyl, halogen, hydroxy or selected such that        R² and R³ together form a ring system;    -   each R⁴ and R⁵ is independently selected from the group        consisting of hydrogen, halogen, hydroxy, optionally substituted        C₁₋₆-alkyl, OC₁₋₆alkyl, aryl-C₁₋₆alkyl, and arylheteroalkyl;    -   L¹ and L² are biradicals independently selected from the group        consisting of —C(R⁶)═C(R⁷), —C(R⁶)═N—, —N═C(R⁶)—, —S—, —NH— and        —O—; wherein only one of L¹ and L² may be selected from the        group consisting of —S—, —NH— and —O—;    -   Y is selected from the group consisting of O, S, and H₂;    -   X is a biradical selected from the group consisting of        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—,        C(R⁶)(R⁷)—O—, —S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—,        —N(R^(N))—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—N(R^(N))—,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —O—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,        S—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, N(R^(N))—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—O, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—S,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—N(R^(N))—, —C(R⁶)(R⁷)—C(R⁶)═C(R⁷)—, and        —C(R⁶)═C(R⁷)—C(R⁶)(R⁷), wherein R⁶ and R⁷ are independently        selected from the group consisting of hydrogen, halogen,        hydroxy, nitro, cyano, NR^(N)R^(N), N(R^(N))—C(O) N(R^(N)),        optionally substituted C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        optionally substituted O—C₁₋₆-alkyl, optionally substituted        O-aryl, optionally substituted O—C₂₋₆-alkenyl, optionally        substituted O—C₂₋₆-alkynyl    -   wherein R^(N) is selected from the group consisting of hydrogen,        and optionally substituted C₁₋₆-alkyl.

The present investigators have found that the compounds of the inventionhave a high affinity and specificity for the M₁ muscarinic receptor. Thecompounds of the invention may be of use in an array of conditionsassociated with the modulation of the M₁ muscarinic receptor subtype.

Typically, the compounds of formula I are such that R¹ is selected fromthe group consisting of optionally substituted C₁₋₆-alkyl, optionallysubstituted C₁₋₆-alkylidene, optionally substituted C₂₋₆-alkenyl,optionally substituted C₂₋₆-alkynyl, optionally substitutedO—C₁₋₆-alkyl, and optionally substituted O—C₂₋₆-alkenyl. R¹ can beselected from the group consisting of optionally substituted C₁₋₆-alkyl,optionally substituted C₁₋₆-alkylidene, optionally substitutedC₂₋₆-alkenyl, optionally substituted O—C₁₋₆-alkyl. R¹ can typically beselected from the group consisting of optionally substituted C₁₋₆-alkyl,optionally substituted C₁₋₆-alkylidene, and optionally substitutedO—C₁₋₆-alkyl. Most typically, R¹ is selected from the group consistingof optionally substituted C₄-alkyl, optionally substituted C₅-alkyl,optionally substituted C₄-alkylidene, and optionally substitutedO—C₁₋₆-alkyl. In a preferred embodiment, R¹ may be unsubstitutedC₄-alkyl, unsubstituted C₅-alkyl, or unsubstituted O—C₃-alkyl, e.g.n-butyl, n-pentyl, or n-propyloxy.

In a particular embodiment of the invention, the compounds of formula Iare such that R¹ is an optionally substituted C₁₋₆-alkyl, selected fromthe group consisting of unsubstituted C₁₋₆-alkyl, and C₁₋₆-alkoxyalkyl.The C₁₋₆-alkoxyalkyl may be C₁₋₃-alkoxyC₁₋₃alkyl. Typically, theC₁₋₆-alkoxyalkyl is selected from methoxypropyl, ethoxyethyl,propyloxymethyl, and methoxyethyl.

In one embodiment of the invention, the compounds of formula I arepiperidines, bicyclic piperidines, 3-4-unsaturated piperidines orbicyclic 3-4-unsaturated piperidines. Within this embodiment, the C₃-C₄bond may be a single bond to form either a piperidine ring or a bicylicpiperidine. Alternatively, piperidine may be 3-4 unsaturated. That is tosay that C₃-C₄ may be a double bond (C₃═C₄) so as to form either a3-4-unsaturated piperidine or bicylic 3-4-unsaturated piperidine.

In another embodiment of the invention, m is 0 and C₃ is absent while C₄is CH, so as to result in an azetidine ring. Bicyclic analogues ofazetidine are also included.

In an alternative embodiment, m is 0 so as to result in a pyrrolidinering or a 3-pyrroline, when C3-C4 is a single bond or a double bond,respectively. Bicyclic analogues of pyrrolidine ring or a 3-pyrrolineare further included. In a further suitable embodiment, m is 2 so as toform a 7-membered ring. In a particular embodiment, m is 1.

In one embodiment, R² and R³ together form a bicyclic ring system suchthat

is selected from the group consisting of

wherein R⁸ is present 0, 1, or 2 times and is independently selectedfrom the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted O—C₁₋₆ alkyl, halogen, hydroxy.

Within such an embodiment, R² and R³ may preferably be selected suchthat R² and R³ together form a ring system such that

is selected from the group comprising

In a more preferred embodiment, the substituents R² and R³ are selectedso that the bicyclic ring is 3-substituted 8-azabicyclo[3.2.1]octane.

However, in a particular embodiment, R² and R³ are independentlyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted O—C₁₋₆ alkyl, halogen and hydroxy.

Thus, in a combination of embodiments of compounds of formula I, C₃-C₄is a single bond, R² and R³ are independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted O—C₁₋₆ alkyl, halogen and hydroxy, and m is 1. Suitably, R²and R³ are hydrogen.

In a further combination, m can be 0, C₃ can be absent, and C₄ can be CHsuch that

In a further combination of embodiments, C₃-C₄ and m are so as to form apiperidine ring, for example, wherein R² and R³ are hydrogen. Inadditional embodiments, C₃-C₄ and m are so as to form a piperidine ring,R² and R³ are hydrogen, and R¹ an unsubstituted C₄-alkyl, anunsubstituted C₅-alkyl, or an O—C₃-alkyl, such as butyl, pentyl, orpropyloxy.

Thus, in one embodiment

is a 4-butyl piperidine.

In another embodiment

is 4-butyl piperidine.

In one embodiment of the invention, C₃-C₄ and m are such as to form anazetidine ring,

R² and R³ are hydrogen, and R¹ is selected from unsubstitued C₄-alkyl,unsubstituted C₅-alkyl, and O—C₃-alkyl. Thus, in one embodiment

is a 4-butylazetidine.

In one aspect of the invention a 3-carbon tether is linking the twonitrogen atoms of the two ring systems of the compounds of formula I.The present investigators have found that this optionally substitutedpropylene spacer unit provides for compounds with highly efficaciousbinding capacity to the cholinergic receptors. More specifically, thecompounds of the invention show agonistic properties at cholinergicreceptors, especially muscarinic receptors.

In one embodiment, the tether

is unsubstituted, meaning that all of R⁴ and R⁵ are hydrogen.

In another embodiment one of the substituents R⁴ is selected from thegroup consisting of C₁₋₆-alkyl, O—C₁₋₆-alkyl, and halogen, while theother two of the substituents R⁴ are hydrogen.

In a combination of embodiments one of the substituents R⁴ is selectedfrom the group consisting of C₁₋₆-alkyl, O—C₁₋₆-alkyl, and halogen,while the other two of the substituents R⁴ are hydrogen, and all of R⁵are hydrogen.

In a preferred embodiment one of the substituents R⁴ is selected fromthe group consisting of methyl, methoxy, ethyl, and fluoro while theremaining R⁴ and R⁵ are all hydrogen.

Typically, when one of the substituents R⁴ is C₁₋₆-alkyl, O—C₁₋₆-alkyl,or halogen, the tether is a 2-substituted-1,3-propylene group.

In a further suitable embodiment, the tether is a2,2-disubstituted-1,3-propylene group, in which one of R⁴ and one of R⁵are typically C₁₋₆-alkyl or fluoro.

Certain embodiments of the invention, wherein the propylene tethercarries one or more substituents possess a stereogenic atom in thepropylene tether. As set forth in the Examples, such chiral compoundsmay be preferred either in racemic or enantiomerically enriched form.Pure enantiomers and racemates are both included in the invention.

X may be a 1-, 2-, or 3-atom linear unit such that, together with theatoms in the ring comprising X, a 5-, 6- or 7-membered ring is formed.As stated, X, within the ring, is a biradical selected from the groupconsisting of —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—,C(R⁶)(R⁷)—O—, —S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—, —N(R^(N))—C(R⁶)(R⁷)—,—C(R⁶)(R⁷)—N(R^(N))—, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,—O—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,S—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,N(R^(N))—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)(R⁸)—C(R⁶)(R⁷)—O,—C(R⁶)(R⁷)—C(R⁶)(R⁷)—S, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—N(R^(N))—,—C(R⁶)(R⁷)—CH═CH— and —CH═CH—C(R⁶)(R⁷).

In a preferred embodiment X is selected from the group consisting of—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—, C(R⁶)(R⁸)—O—,—S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—, —N(R^(N))—C(R⁶)(R⁷)—,—C(R⁶)(R⁷)—N(R^(N))—.

In a more preferred embodiment X is selected from the group consistingof —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —O—C(R⁶)(R⁷)—, C(R⁶)(R⁸)—O—, and—C(R⁶)═C(R⁷)—.

R⁶ and R⁷ are optional substituents of the ring system. An array ofsubstituents is anticipated by the present investigators and are knownto the person skilled in the art. The substituents R⁶ and R⁷ mayindependently be selected from the group consisting of hydrogen,halogen, hydroxy, nitro, cyano, NR^(N)R^(N), N(R^(N))—C(O) N(R^(N)),optionally substituted C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,optionally substituted O—C₁₋₆-alkyl, optionally substituted O-aryl,optionally substituted O—C₂₋₆-alkenyl, optionally substitutedO—C₂₋₆-alkynyl.

Suitably, when the substituents R⁶ and R⁷ occur within the definition ofX, they are typically selected from hydrogen, halogen, hydroxy andC₁₋₆-alkyl. More typically, R⁶ and R⁷, when consituting part of thedefinition of X, are both hydrogen.

In one embodiment, Y is selected from the group consisting of O, S andH₂.

In a preferred embodiment, Y is O.

As stated, L¹ and L² are biradicals independently selected from thegroup consisting of —C(R⁷)═C(R⁸), —C(R⁷)═N—, —N═C(R⁷)—, —S—, —NH— and—O—; wherein only one of L¹ and L² may be selected from the groupconsisting of —S— and —O—. Typically, L¹ and L² are such that

is an aromatic or heteroaromatic ring. In one embodiment, L¹ and L² areindependently selected from the group consisting of —C(R⁶)═C(R⁷)—,—C(R⁶)═N—, —N═C(R⁷)—, and —S—; wherein only one of L¹ and L² is —S—. Inanother embodiment, at least one of L¹ and L² is C(R⁶)═C(R⁷). In yetanother embodiment, L¹ and L² are so as to form a 6-membered ring. Instill another embodiment, both of L¹ and L² are —C(R⁶)═C(R⁷)—.

Suitably, when the substituents R⁶ and R⁷ occur within the definition of

they are typically selected from hydrogen, halogen, hydroxy, C₁₋₆-alkyland O—C₁₋₆-alkyl.

Preferably, when the substituents R⁶ and R⁷ occur within the definitionof

they are selected from hydrogen, fluoro, chloro, methyl, and methoxy.

Thus, in a combination of embodiments, the compounds of the inventionare of formula Ia

wherein R¹ is selected from the group consisting of optionallysubstituted C₁₋₆-alkyl, optionally substituted C₁₋₆-alkylidene,optionally substituted C₂₋₆-alkenyl, optionally substitutedC₂₋₆-alkynyl, optionally substituted O—C₁₋₆-alkyl, optionallysubstituted O—C₂₋₆-alkenyl; and R², R³, R⁴, X, Y, R⁶, and R⁷ are asdefined supra.

In another combination of embodiments, the compounds of the inventionare of formula Ia, wherein X is selected from the group consisting of—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—, C(R⁶)(R⁸)—O—,—S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—, —N(R^(N))—C(R⁶)(R⁷)—,—C(R⁶)(R⁷)—N(R^(N))—,

-   -   wherein R⁶ and R⁷ are suitably hydrogen.

In a further combination of embodiments, the compounds of the inventionare of formula Ia, wherein Y is O.

In yet another combination of embodiments, the compounds of theinvention are of formula Ia, wherein R⁴ is selected from hydrogen,C₁₋₆-alkyl, O—C₁₋₆-alkyl, and halogen.

In a further combination of embodiments, the compounds of the inventionare of formula Ia, wherein R⁶ and R⁷ are selected from hydrogen,halogen, hydroxy, C₁₋₆-alkyl and O—C₁₋₆-alkyl.

In another combination of embodiments, the compounds of the inventionare of formula Ia, wherein the optionally substituted C₁₋₆-alkyl isselected from the list comprising unsubstituted C₁₋₆-alkyl, andC₁₋₆-alkoxyalkyl, and wherein Y is selected from the group consisting ofO and H₂, and wherein X is selected from the group consisting of—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—O—,—S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—, and wherein L¹ and L² are independentlyselected from the group consisting of —C(R⁶)═C(R⁷)—, —C(R⁶)═N—, and—N═C(R⁷)—, and wherein R⁴ selected from the group consisting ofhydrogen, halogen, hydroxy, optionally substituted C₁₋₆-alkyl, andoptionally substituted O—C₁₋₆alkyl.

In a further combination of embodiments, the compounds of the inventionare optionally substituted1-[3-(4-alkylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolines,optionally substituted1-[3-(4-alkylpiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones,optionally substituted1-[3-(4-alkylpiperidin-1-yl)propyl]-1H-quinolin-2-ones, optionallysubstituted4-[3-(4-alkylpiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-ones,optionally substituted4-[3-(4-alkylpiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-ones;optionally substituted1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-1,2,3,4-tetrahydroquinolinesoptionally substituted1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones,optionally substituted1-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-1H-quinolin-2-onesoptionally substituted4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-ones;optionally substituted4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-ones;optionally substituted1-[3-(3-alkylazetidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-ones,optionally substituted1-[3-(3-alkylazetidin-1-yl)propyl]-1H-quinolin-2-ones, optionallysubstituted1-[3-(3-alkylazetidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolines;optionally substituted4-[3-(3-alkylazetidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-ones;optionally substituted4-[3-(3-alkylazetidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-ones.

Suitable embodiments of the compounds of the invention may be selectedfrom the group consisting of1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-3,4-dihydro-1H-quinolin-2-one;4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]thiazin-3-one;4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;6-Acetyl-4-[3-(4-butyl-pipperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine;and4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine;(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one;(R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one;(R)-4-[3-(4-Butylidene-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one;(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one;(R)-4-[2-Methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichlooro-7-methyl-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butyl-piperidin-1-yl)propyl]-6,8-dimetethyl-4H-benzo[1,4]oxazin-3-one(81MF2237F);6-tert-Butyl-4-[3-(4-butyl-piperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-7-nitro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-7-chloro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-7,8-difluoro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-4H-pyrido[4,3-b][1,4]thiazin-3-one;4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one;4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one;4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(3-Butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one;6-Bromo-4-[3-(4-butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butylpiperidin-1-yl)propyl]-8-isopropyl-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxy-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one;(−)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin)-2-methoxypropyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;4-[2-(4-Butylpiperidin-1-ylmethyl)allyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-fluoropropyl]-4H-benzo[1,4]oxazin-3-one;(S)-4-[3-(4-Butyl-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R)-6-Fluoro-4-[2-methyl-3-(4-propoxy-piperidin-1-yl-propryl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methyl-propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;(R)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylpiperidin-1-yl)2-methylpropyl]-7-Fluoro-4H-benzo[1,4]oxazin-3-one;(R)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one;(R)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methyl-propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R)-6-Methoxy-4-[2-methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R)-6-Methoxy-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R)-6-Methyl-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-propryl]-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;(R)-4-[3-(3-Pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one;1-[3-(4-Propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one;6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one;(R,S)-6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-3,4-dihydro-1H-quinolin-2-one;6-Methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one;6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one;(R,S)-6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one;6-Fluoro-7-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one;(R,S)-6-Fluoro-7-methyl-1-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one;1-[3(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one;6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-1H-quinolin-2-one;1-[3-(4-Propoxypiperidin-1-yl)propyl]-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-1H-quinolin-2-one;1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-1H-quinolin-2-one;1-[3-(4-Butyl-piperidin-1-yl)propyl]-7-methyl-1H-quinolin-2-one;(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-1H-quinolin-2-one;(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-1H-quinolin-2-one;1-[3-(4-Allyloxypiperidin-1-yl)propyl]-1H-quinolin-2-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-6-methyl-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methyl-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-6-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one;(R,S)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1.4]oxazin-3-one;(R,S)-3-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one;(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3H-benzothiazol-2-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one;(R,S)-3-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3H-benzothiazol-2-one;(R,S)-3-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3H-benzothiazol-2-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one;(R,S)-1-2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one;(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one;(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-6-methoxy]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-4H-benzo[1,4]oxazin-3-one;(R,S)-6,7-Difluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(3-Butoxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;(R,S)-6-Fluoro-4-{3-[3-(2-methoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1,4]oxazin-3-one,(R,S)-4-[3-(3-Butylazetidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;(R,S)-6-Fluoro-4-[2-methyl-3-(3-propoxyazetidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one;(R,S)-4-[3-(3-Butylazetidin-1-yl)-2-methoxypropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one;4-[3-(4-Butyl-3-fluoropiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one.

In another aspect, disclosed herein is a compound of formula (I), andsalts and isomers thereof

wherein:

-   -   m is 0, 1 or 2;    -   C₃-C₄ is CH₂—CR¹R⁹ or CH═CR¹ or C₄ is CR¹R⁹ and C₃ is absent;    -   each R¹ and each R⁹ is separately selected from the group        consisting of hydrogen, halogen, hydroxy, straight- or        branched-chain optionally substituted C₁₋₆ alkyl, straight- or        branched-chain optionally substituted C₂₋₆ alkenyl, straight- or        branched-chain optionally substituted C₂₋₆ alkynyl, straight- or        branched-chain optionally substituted C₁₋₆ alkylidene, straight-        or branched-chain optionally substituted C₁₋₆ alkoxy, straight-        or branched-chain optionally substituted C₁₋₆ heteroalkyl,        straight- or branched-chain optionally substituted C₁₋₆        aminoalkyl, straight- or branched-chain optionally substituted        C₁₋₆ haloalkyl, straight- or branched-chain optionally        substituted C₁₋₆ alkoxycarbonyl, straight- or branched-chain        optionally substituted C₁₋₆ hydroxyalkoxy, straight- or        branched-chain optionally substituted C₁₋₆ hydroxyalkyl,        straight- or branched-chain optionally substituted C₁₋₆        alkylthio, straight- or branched-chain optionally substituted        —O—C₂₋₆ alkenyl, straight- or branched-chain optionally        substituted —O—C₂₋₆ alkynyl, straight- or branched-chain        optionally substituted C₃₋₆ alkenylalkoxy, straight- or        branched-chain optionally substituted C₁₋₆ alkyloxyimino,        straight- or branched-chain optionally substituted C₁₋₆        alkyloxyamino, optionally substituted —O—CH₂—C₅₋₆ aryl,        —C(O)NR¹⁰R¹¹, —CR¹⁰R¹¹R¹², —OC(O)R¹⁰, straight- or        branched-chain optionally substituted —(O)(CH₂)_(s)NR¹¹R¹²,        straight- or branched-chain optionally substituted        —(CH₂)_(s)NR¹¹R¹², straight- or branched-chain optionally        substituted —OC(O)O(CH₂)_(s)CH₃, straight- or branched-chain        optionally substituted —S—C₁₋₆-alkyl, straight- or        branched-chain optionally substituted —S—C₂₋₆-alkenyl, and        straight- or branched-chain optionally substituted        —S—C₂₋₆-alkynyl, each of which may be optionally substituted        with one or more substituents R_(x);    -   each R¹⁰ is separately selected from the group consisting of        hydrogen, straight- or branched-chain C₁₋₆ alkyl, straight- or        branched-chain C₂₋₆ alkenyl, straight- or branched-chain C₂₋₆        alkynyl, straight- or branched-chain C₂₋₆ heteroalkyl, straight-        or branched-chain C₂₋₆ aminoalkyl, straight- or branched-chain        C₂₋₆ haloalkyl, straight- or branched-chain C₁₋₆ alkoxycarbonyl,        straight- or branched-chain C₂₋₆ hydroxyalkyl, C₃₋₈ cycloalkyl,        —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo, C₅₋₆ aryl,        C₅₋₆ heteroaryl, C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl,        —C(O)NR¹¹R¹², —CR¹¹R¹²R¹³, and straight- or branched-chain        —(CH₂)_(s)NR¹¹R¹²;    -   each s is separately selected to be an integer from 1 to 8;    -   each R¹¹ and each R¹² is separately selected from the group        consisting of hydrogen, straight- or branched-chain C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, and C₅₋₆ heteroaryl, or each R¹¹ and R¹²        together form a C₃₋₈ cycloalkyl or C₃₋₈ heterocycloalkyl;    -   R¹³ is selected from the group consisting of hydrogen, halogen,        straight- or branched-chain C₁₋₆ alkyl, formyl, and C₃₋₆        cycloalkyl;    -   each R_(x) is separately selected from the group consisting of        hydrogen, halogen, hydroxy, straight- or branched-chain        optionally substituted C₁₋₆ alkyl, straight- or branched-chain        optionally substituted C₁₋₆ alkoxy, optionally substituted C₃₋₈        cycloalkyl, optionally substituted C₃₋₈ heterocyclyl, and        straight- or branched-chain optionally substituted C₁₋₆        alkylidene;    -   R² and R³ are separately selected from the group consisting of        hydrogen, optionally substituted C₁₋₆ alkyl, optionally        substituted O—C₁₋₆ alkyl, halogen, hydroxy or selected such that        R² and R³ are covalently linked together to form a ring system;    -   each R⁴ and each R⁵ are separately selected from the group        consisting of hydrogen, halogen, hydroxy, optionally substituted        C₁₋₆-alkyl, optionally substituted O—C₁₋₆alkyl, optionally        substituted aryl-C₁₋₆alkyl, and optionally substituted        arylheteroalkyl;    -   L¹ and L² are biradicals separately selected from the group        consisting of —C(R⁶)═C(R⁷), —C(R⁶)═N—, —N═C(R⁶)—, —S—, —NH— and        —O—; wherein only one of L¹ and L² may be selected from the        group consisting of —S—, —NH— and —O—;    -   Y is selected from the group consisting of O, S, and H₂; and    -   X is a biradical selected from the group consisting of        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷), —O—C(R⁶)(R⁷)—,        C(R⁶)(R⁷)—O—, —S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—,        —N(R^(N))—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—N(R^(N))—,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —O—C(R⁶(R⁷)—C(R⁶)(R⁷)—,        S—C(R⁶)(R⁷)—C(R⁶)(R⁷)—, N(R^(N))—C(R⁶)(R⁷)—C(R⁶)(R⁷)—,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—O, —C(R⁶)(R⁷)—C(R⁶)(R⁷)—S,        —C(R⁶)(R⁷)—C(R⁶)(R⁷)—N(R^(N))—, —C(R⁶)(R⁷)—C(R⁶)═C(R⁷)—, and        —C(R⁶)═C(R⁷)—C(R⁶)(R⁷), wherein R⁶ and R⁷ are separately        selected from the group consisting of hydrogen, halogen,        hydroxy, nitro, cyano, NR^(N)R^(N), N(R^(N))—C(O) N(R^(N)),        optionally substituted C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        optionally substituted O—C₁₋₆-alkyl, optionally substituted        O-aryl, optionally substituted O—C₂₋₆-alkenyl, optionally        substituted O—C₂₋₆-alkynyl,    -   wherein R^(N) is selected from the group consisting of hydrogen,        and optionally substituted C₁₋₆-alkyl.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound of formula (I), as disclosed above, or apharmaceutically acceptable salt, ester, or prodrug thereof.

In some embodiments, disclosed herein is a compound of formula (I),wherein:

-   -   at least one of R₁ or R₉ is selected from the group consisting        of hydroxy, straight- or branched-chain optionally substituted        C₁₋₆ alkoxy, straight- or branched-chain optionally substituted        C₁₋₆ alkyl, straight- or branched-chain optionally substituted        C₂₋₆ alkenyl, straight- or branched-chain optionally substituted        C₃₋₆ alkenylalkoxy, straight- or branched-chain optionally        substituted C₁₋₆ alkyloxyimino, and straight- or branched-chain        optionally substituted —OC(O)O(CH₂)_(s)CH₃; and    -   R_(x) is selected from the group consisting of halogen,        optionally substituted C₃₋₈ cycloalkyl, optionally substituted        straight- or branched-chain C₁₋₆ alkyl, optionally substituted        C₁₋₆ alkoxy and optionally substituted straight- or        branched-chain C₂₋₆ alkenyl

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

In some embodiments, disclosed herein is a compound of formula (I),wherein:

-   -   the at least one of R¹ or R⁹ is selected from the group        consisting of hydroxyl methyl, ethyl, propyl, butyl, methoxy,        ethoxy, propoxy, butoxy, ethenylmethoxy, ethenylethoxy,        ethenylpropoxy, iminobutoxy, iminomethoxy, iminoethoxy,        iminopropoxy, iminobutoxy; and —OC(O)O(CH₂)₂CH₃; and    -   R_(x) is selected from the group consisting of cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, halogen, and ethenyl.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

In some embodiments, disclosed herein is a compound of formula (I),wherein:

-   -   X is selected from the group consisting of —CH₂O— and —CH₂CH₂—;    -   L¹ and L² is —C(R⁶)═C(R⁷)—; and    -   each R⁶ and each R⁷ are separately selected from the group        consisting of H, halogen, methyl, and methoxy.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein R², R³, R⁹, m, and C₃-C₄ areselected such that

is selected from the group consisting of

-   -   wherein R⁸ is present 0, 1, or 2 times and is independently        selected from the group consisting of optionally substituted        C₁₋₆ alkyl, optionally substituted O—C₁₋₆ alkyl, halogen,        hydroxy.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein C₃-C₄, m, R², R³, and R⁹ arehydrogen or selected such that R² and R³ together form a ring systemsuch that

is selected from the group consisting of

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein R² and R³ are separatelyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted O—C₁₋₆ alkyl, halogen and hydroxy.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein m is 1.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein m is 0, C₃ is absent, and C₄is CH such that

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1 wherein X is selected from the groupconsisting of —C(R⁶)(R⁷)—C(R⁶)(R⁷)—, —C(R⁶)═C(R⁷)—, —O—C(R⁶)(R⁷)—,—C(R⁶)(R⁷)—O—, —S—C(R⁶)(R⁷)—, —C(R⁶)(R⁷)—S—, —N(R^(N))—C(R⁶)(R⁷)—,—C(R⁶)(R⁷)—N(R^(N))—.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1 wherein Y is selected from the groupconsisting of O and H₂.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1 wherein L¹ and L² are independentlyselected from the group consisting of —C(R⁶)═C(R⁷)—, —C(R⁶)═N—, and—N═C(R⁷)—.

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 1, wherein R¹ is selected from the groupconsisting of:

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

The compound according to claim 13 selected from the group consistingof:

Disclosed herein is a pharmaceutical composition comprising an effectiveamount of a compound disclosed in the above paragraph or apharmaceutically acceptable salt, ester, or prodrug thereof.

In another aspect, disclosed herein is a method of treating a disease ina mammal, wherein modulation of the activity of a cholinergic receptoris associated with a physiologically beneficial response in said diseaseof said mammal, said method comprising administering an effective amountof a compound of formula (I).

In some embodiments, the cholinergic receptor is a muscarinic receptor.

In some embodiments, the cholinergic receptor is a muscarinicM₁-receptor subtype.

In some embodiments, the cholinergic receptor is the muscarinicM₄-receptor subtype.

In some embodiments, the physiologically beneficial response isassociated with the selective modulation of the muscarinic M₁-receptorsubtype in relation to the muscarinic M₂- or M₃-receptor subtypes.

In some embodiments, the compound is a muscarinic agonist.

In another aspect, disclosed herein is a method of increasing anactivity of a cholinergic receptor comprising contacting the cholinergicreceptor or a system containing the cholinergic receptor with aneffective amount of at least one compound of formula (I).

In another aspect, disclosed herein is a method of treating orpreventing or alleviating the symptoms associated with a disorder in amammal, comprising the administration of an effective amount of at leastone compound of formula (I), said disorder associated with a muscarinicreceptor, such as M₁ muscarinic receptor subtype.

In some embodiments, the disorder is selected from the group consistingof cognitive impairment, forgetfulness, confusion, memory loss,attentional deficits, deficits in visual perception, depression, pain,sleep disorders, psychosis, and increased intraocular pressure.

In some embodiments, the disorder is selected from the group consistingof neurodegenerative diseases, Alzheimer's disease, Parkinson's disease,schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de laTourette's Syndrome, Downs Syndrome, Pick disease, dementia, clinicaldepression, age-related cognitive decline, attention-deficit disorder,sudden infant death syndrome, and glaucoma.

In some embodiments, the disease or disorder is a mental disorder andthe physiologically beneficial response is due to modulation in terms ofM₁ agonism; M₁ and M₄ agonism; both M₁ agonism and D₂ antagonism; or M₁and M₄ agonism and D₂ antagonism.

The compounds of the invention have the ability to increase cholinergicreceptor activity or activate cholinergic receptors. Cholinergicreceptor activity includes signaling activity or any other activity thatis directly or indirectly related to cholinergic signalling oractivation. The cholinergic receptors include muscarinic receptors,especially the m1 or m4 subtype of muscarinic receptors. The muscarinicreceptor can be, for example, in the central nervous system, peripheralnervous system, gastrointestinal system, heart, endocrine glands, orlungs. The muscarinic receptor can be a wild-type, truncated, mutated,or modified cholinergic receptor.

Kits comprising the compounds of the present invention, and instructionsfor practicing a method of the invention, for example, increasingcholinergic receptor activity or activating cholinergic receptors, arealso provided.

The system containing the cholinergic receptor may, for example, be asubject such as a mammal, non-human primate or a human. The system mayalso be an in vivo or in vitro experimental model, such as a cellculture model system that expresses a cholinergic receptor, a cell-freeextract thereof that contains a cholinergic receptor, or a purifiedreceptor. Non-limiting examples of such systems are tissue culture cellsexpressing the receptor, or extracts or lysates thereof.

Cells that may be used in a method of the invention include any cellcapable of mediating signal transduction via cholinergic receptors, suchas the ml muscarinic receptor, either via endogenous expression ofreceptor (certain types of neuronal cells lines, for example, nativelyexpress the m1 receptor), or such as following introduction of anexogenous gene into the cell, for example, by transfection of cells withplasmids containing the receptor gene. Such cells are typicallymammalian cells (or other eukaryotic cells, such as insect cells orXenopus oocytes), because cells of lower life forms generally lack theappropriate signal transduction pathways for the present purpose.Specific non-limiting examples of suitable cells include: the mousefibroblast cell line NIH 3T3 (ATCC CRL 1658), which responds totransfected m1 receptors by increased growth; RAT 1 cells (Pace et al.,Proc. Natl. Acad. Sci. USA 88:7031-35 (1991)); and pituitary cells(Vallar et al., Nature 330:556-58 (1987)). Other useful mammalian cellsinclude but are not limited to HEK 293 cells, CHO cells and COS cells.

The compounds of the present invention also have the ability to reduceintraocular pressure and therefore can be used in the treatment of suchdiseases associated with intraocular pressure, e.g., glaucoma. Glaucomais a disease in which an abnormality is observed in thecirculation-control mechanism of the aqueous humor filling up theanterior chamber, i.e., the space formed between the cornea and thelens. This leads to an increase in the volume of the aqueous humor andan increase in intraocular pressure, consequently leading to visualfield defects and even to loss of eyesight due to the compulsion andcontraction of the papillae of the optic nerve.

Accordingly, the invention also provides methods of treating a diseasein a mammal, such as a human, wherein modulation of the activity of acholinergic receptor is associated with a physiologically beneficialresponse in said disease of said mammal. In one embodiment, a methodincludes administering an effective amount of a compound of formula I,as defined supra, to achieve a physiologically beneficial response.Typically, the cholinergic receptor is a muscarinic receptor, moretypically the cholinergic receptor is a muscarinic M₁-receptor subtype.Alternatively, the cholinergic receptor is the muscarinic M₄-receptorsubtype.

The invention further provides methods of treating or preventing oralleviating the symptoms associated with a disorder in a mammal, such asa human. In one embodiment, a method includes the administration of aneffective amount of the compound of formula I, said disorder associatedwith a muscarinic receptor, such as the M₁ muscarinic receptor subtype,to treat or prevent or alleviate one or more symptoms associated withthe disorder.

The physiologically beneficial response is typically associated with theselective modulation of the muscarinic M₁-receptor subtype in relationto the muscarinic M₂- or M₃-receptor subtypes. In one embodiment, thecompound in the method of the invention is a muscarinic agonist.

The disease or disorder treated by the compounds of the invention istypically a mental disorder and the physiologically beneficial responseis due to modulation in terms of M₁ agonism; M₁ and M₄ agonism; both M₁agonism and D₂ antagonism; or M₁ and M₄ agonism and D₂ antagonism.

A further and related aspect of the invention relates to methods ofincreasing an activity of a cholinergic receptor. In one embodiment, amethod includes contacting the cholinergic receptor or a systemcontaining the cholinergic receptor with an effective amount of at leastone compound as defined supra to increase an activity of a cholinergicreceptor.

As can be ascertained from the above discussion, the compounds of theinvention are intended, at least in part, for use as pharmaceuticalmedicaments. Thus, the invention provides compositions comprising i) oneor more compounds of formula I, as defined supra; and ii) at least onepharmaceutically acceptable excipient or carrier. As the inventionrelates to the use of a compound of formula I, as defined supra, theinvention also provides a compound of formula I, a pharmaceuticallyacceptable salt thereof, a stereoisomer thereof, or a pharmaceuticalcomposition comprising either entity, for the preparation of amedicament for the treatment of diseases or disorders associated with acholinergic receptor or ligand thereof.

The invention thus relates, in part, to a method of treating orpreventing or alleviating one or more symptoms associated with adisorder in a mammal, such as a human. In one embodiment, a methodincludes the administration of an effective amount of the compound offormula I, said disorder associated with a muscarinic receptor, such asthe M₁ muscarinic receptor subtype, to prevent or alleviate one or moresymptoms. Disorders include those selected from the group consisting ofcognitive impairment, forgetfulness, confusion, memory loss, attentionaldeficits, deficits in visual perception, depression, pain, sleepdisorders, psychosis, and increased intraocular pressure. Disorders alsoinclude those selected from the group consisting of neurodegenerativediseases, Alzheimer's disease, Parkinson's disease, schizophrenia,Huntington's chorea, Friederich's ataxia, Gilles de la Tourette'sSyndrome, Downs Syndrome, Pick disease, dementia, clinical depression,age-related cognitive decline, attention-deficit disorder, sudden infantdeath syndrome, and glaucoma. Consequently, the invention furtherrelates to a use of a compound of formula I, a pharmaceuticallyacceptable salt thereof, a stereoisomer thereof, or a pharmaceuticalcomposition comprising either entity, for the preparation of amedicament for the treatment of diseases or disorders including thoseselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gillesde la Tourette's Syndrome, Down Syndrome, Pick disease, dementia,clinical depression, age-related cognitive decline, cognitiveimpairment, forgetfulness, confusion, memory loss, attentional deficits,deficits in visual perception, depression, pain, sleep disorders,psychosis, sudden infant death syndrome, increased intraocular pressureand glaucoma.

Compounds according to the invention may be used alone at appropriatedosages defined by routine testing in order to obtain optimalpharmacological effect on a muscarinic receptor, in particular themuscarinic M₁ or M₄ receptor subtype, while minimizing any potentialtoxic or otherwise unwanted effects. In addition, co-administration orsequential administration of other agents that improve the effect of thecompound may, in some cases, be desirable.

The pharmacological properties and selectivity of the compounds of theinvention for specific muscarinic receptor subtypes may be demonstratedby a number of different assay methods using, for example, recombinantreceptor subtypes, the human receptors as available, e.g., conventionalsecond messenger or binding assays. A particularly convenient functionalassay system is the receptor selection and amplification assay (R-SATassay) in U.S. Pat. No. 5,707,798, which describes a method of screeningfor bioactive compounds by utilizing the ability of cells transfectedwith receptor DNA, e.g., coding for the different muscarinic subtypes,to amplify in the presence of a ligand of the receptor. Cellamplification is detected as increased levels of a marker also expressedby the cells.

The invention is disclosed in further detail in the following examples.

EXAMPLES Example 1 Synthetic Chemistry

General Analytical LC-MS Procedures

Procedure 1:

Spectra were obtained using a HP1100 LC/MSD-instrument. A set-up with abinary pump, auto sampler, column oven, diode array detector, andelectro spray ionisation interface was used. A reversed phase column(C18 Luna 3μ, 75×4.6 mm ID) with a guard column cartridge system wasused. The mobile phase was MeCN/8 mM aqueous ammonium acetate. A15-minute gradient program was used, starting at 70% MeCN over 12minutes to 95% MeCN, over 1 minute to 70% MeCN, hold for 2 minutes. Theflow rate was 0.6 ml/min.

Procedure 2:

Spectra were obtained using a Waters LC/ZMD-instrument. A set-up with a600 gradient pump, 2700 sample manager, 996 diode array detector, andelectro spray ionisation interface was used. A reversed phase column(C18 X-Terra 5μ, 50×4.6 mm ID) with a guard column cartridge system wasused. The mobile phase was MeCN/10 mM aqueous ammonium acetate. A14-minute gradient program was used; starting at 30% MeCN, over 10minutes to 95% MeCN, hold for 2 minutes, over 0.5 minutes to 30% MeCN,hold for 4.5 minutes. The flow rate was 1 ml/min.

General Preparative LC-MS Procedures

Procedure 1:

Preparative purification was performed on a Waters auto purificationsystem (600 pumps, 2700 sample manager, 996 PDA detector, ZMD massspectrometer).

The columns used were YMC C18 J'sphere ODS H80. Buffer A was 0.15% TFAin water, buffer B was 0.15% TFA in MeCN/water 95/5. The columns wereoperated at 17 ml/min. Following an initial hold of 2.5 min at 30%buffer B, compounds were separated using a gradient af 30-100% buffer Bin 8.5 min. A dual column set-up with two pumps was used to equilibrateone column, while running on the other.

Procedure 2:

Preparative purification was performed on Waters Delta 4000 preparativesystem, Water 2487 dual absorbance detector, and Waters Fractioncollector II. The column used was a Luna 15 μm C18, 250×21.2 mm. Thefollowing mobile phases were used: H₂O/MeCN ammonium acetate buffer (25nM) or H₂O/MeCN TFA buffer (25 nM).

Heating with microwave irradiation was performed with a Smith Creatorsingle-mode cavity (Personal Chemistry AB, Uppsala, Sweden) producingcontinuous irradiation at 2.45 GHz. The microwave-assisted reactionswere performed in caped Smith process vials with a magnetic stirringbar. To secure sufficient irradiation absorption the liquid samplevolume was ≧0.5 mL.

Cation exchange CC was performed with Varian BOND ELUT (mega BE-SCX, 1g, 6 ml) columns. After applying the compound to the column, it wasfirst washed with MeOH (2 column volumes) and thereafter the desiredcompound was eluted applying 2 column volumes of an NH₄OH (25% NH₃ inH₂O)/MeOH mixture (1:9).

(R,S)-1-(4-Butylpiperidin-1-yl)-3-chloropropan-2-ol (101IS93-1)

A 4 mL vial was charged with 4-butylpiperidine (0.29 g, 2.0 mmol) andepichlorohydrin (0.190 g, 2.1 mmol) and was shaken at rt for 4 h. Theresulting thick oil was purified by flash chromatography (SiO₂;CH₂Cl₂/acetone/MeOH 85/10/5) to yield the title compound as an oil (0.31g, 64%). ¹H NMR (CDCl₃) δ 3.95-3.85 (m, 1H), 3.60-3.48 (m, 1H),2.97-2.88 (m, 1H), 2.82-2.72 (m, 1H), 2.46-2.35 (m, 1H), 2.30-2.20 (m,1H), 1.98-1.88 (m, 1H), 1.70-1.58 (m, 2H), 1.35-1.08 (m, 9H), 0.88 (t,J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) δ 66.7, 61.5, 55.9, 53.1, 47.4, 36.4,35.8, 32.9, 32.6, 29.2, 23.1, 14.3.

(R,S)-4-Butyl-1-(3-chloro-2-fluoropropyl)piperidine (101IS93-2)

DAST (1.9 mmol, 230 μl) was added drop wise to a solution of1-(4-butylpiperidin-1-yl)-3-chloropropan-2-ol (101IS93) (0.31 g, 1.28mmol) in CH₂Cl₂ (5 mL). After 2 h the reaction was quenched by theaddition water (5 mL) and the organic phase was extracted with CH₂Cl₂(2×15 mL) and the combined organic phase was dried (Na₂SO₄), filtered,concentrated under reduced pressure and the residue was purified byflash chromatography (SiO₂; heptane/EtOAc 60:40) to yield the titlecompound as an oil (0.025 g, 9%); ¹H NMR (CDCl₃) δ 4.79 (dm, J=48 Hz,1H), 3.78-3.60 (m, 2H), 2.92-2.83 (m, 2H), 2.72-2.56 (m, 2H), 2.15-2.00(m, 2H), 1.69-1.58 (m, 2H), 1.35-1.16 (m, 9), 0.88 (t, J=6.8 Hz); ¹³CNMR (CDCl₃) δ 91.1 (d, J=111 Hz), 59.9 (d, J=22 Hz), 55.2, 54.9, 44.9(d, J=25 Hz), 36.4, 35.6, 32.7, 32.6, 29.2, 23.1, 14.3.

General Procedure 1 (GP1)

To a flask or vial was charged 2-aminophenol (1.0 equiv) disolved in DMF(0.1 g/mL) and 2-Chloroacetyl chloride (1.1 equiv) was added. Thereaction was stirred in rt for 12-20 hours and K₂CO₃ (2.1 equiv) wasadded. The reaction was stirred in rt for another 12-20 hours thenevaporated to dryness, redisolved in water (10 mL) and extracted usingEtOAc (3×20 mL). The combined organic phases concentrated to a crudethat was used directly or purified by CC (Heptane:EtOAc).

4H-Pyrido[4,3-b][1,4]thiazin-3-one (81MF939a)

3-Amino-4-thiopyridine (0.10 g, 0.79 mmol) and 2-Chloroacetyl chloride(0.098 g, 0.87 mmol) and K₂CO₃ (0.23 g, 1.66 mmol) were mixed accordingto GP1 to give the title compound as a crude (81MF939a) (0.087 g)

8-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF45)

2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetylchloride (0.25 g, 2.2 mmol) and K₂CO₃ (0.583 g, 4.2 mmol) were mixedaccording to GP1 to give the title compound as a crude (95MF45) (0.29 g)

7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12)

2-Amino-5-flourophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetylchloride (10.1 g, 89 mmol) and K₂CO₃ (23.5 g, 170 mmol) were mixedaccording to GP1. CC (SiO₂; Heptane/EtOAc 4:1-4) to give the titlecompound (111MF12) (12.6 g, 93%); ¹H NMR (DMSO) d 10.68 (s, 1H,6.83-6.91 (m, 2H, 6.75-6.80 (m, 1H, 4.57 (s, 2H; ¹³C NMR (DMSO) d 164.2,157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3(d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.

7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082A)

6-Amino-2,3-diflourophenol (81KK30a) (0.113 g, 0.78 mmol),2-chloroacetyl chloride (0.10 g, 0.89 mmol) and K₂CO₃ (0.226 g, 1.6mmol) were mixed according to GP1 to give the title compound as a crude(81MF2082A) (0.12 g)

6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44)

2-Amino-4-bromo-6-flourophenol (95MF2084) (0.078 g, 0.38 mmol),2-chloroacetyl chloride (0.048 g, 0.42 mmol) and K₂CO₃ (0.11 g, 0.79mmol) were mixed according to GP1 to give the title compound as a crude(95MF44) (0.091 g)

8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83)

Crude 2-Amino-6-isopropylphenol (95MF80(2240) (0.16 g, 1.1 mmol),2-chloroacetyl chloride (0.14 g, 1.2 mmol) and K₂CO₃ (0.32 g, 2.3 mmol)were mixed according to GP1 to give the title compound as a crude(95MF83) (0.115 g).

6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225)

6-Amino-2.4 dichloro-3-metylphenol (1.9 g, 10 mmol), 2-chloroacetylchloride (1.2 g, 11 mmol) and K₂CO₃ (3.0 g, 22 mmol) were mixedaccording to GP1 to give the title compound as a crude (80MF2225) (2.33g).

6,8-Dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one (95MF46)

6-Amino-2.4-dichloro-3-etylphenol (95MF2226) (0.293 g, 1.5 mmol),2-chloroacetyl chloride (0.19 g, 1.7 mmol) and K₂CO₃ (0.44 g, 3.2 mmol)were mixed according to GP1 to give the title compound as a crude(95MF46) (0.34 g).

7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one (97KK40)

3-Fluoro-4-methylaniline (1.247 g, 9.96 mmol), 3-chloropropionylchloride (1.269 g, 9.99 mmol), and K₂CO₃ (1.450 g, 10.5 mmol) in MeCN(10 mL) were stirred at 40° C. for 3 h. The reaction mixture wasquenched with 4M HCl and the product extracted into CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Theresidue (1.168 g) was heated to 145° C. and small portions of AlCl₃(3.538 g, 26.5 mmol) were added over a period of 30 min. The reactionmixture was then cooled and 4M HCl added under stirring followed byextraction of the product into CH₂Cl₂. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby flash CC (SiO₂; CH₂Cl₂/MeOH 40:1) to give the title compound (97KK40)(0.201 g, total yield 11%). ¹H NMR (CDCl₃) d 8.15 (br s, 1H), 6.94 (d,J=7.8 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 2.91-2.87 (m, 2H), 2.62-2.60 (m,2H), 2.19 (d, J=1.8 Hz, CH₃).

6-Fluoro-1H-quinolin-2-one (97KK38)

DDQ (0.38 g, 1.7 mmol) was added to a solution of6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.18 g, 1.1 mmol) in dioxane (25mL) and the resulting solution was refluxed for 16 h. The mixture wasconcentrated, and sat aqueous Na₂CO₃ (25 mL) was added followed byextraction into an organic mixture (MeOH:CH₂Cl₂; 1:10, 3×50 mL). Thecombined organic phase was dried (Na₂SO4), filtered, concentrated underreduced pressure and purified by flash CC (SiO₂; CH₂Cl₂/MeOH 20:1) togive the title compound (0.056 g, 31%). ¹H NMR (DMSO-D₆) δ 11.8 (brs,1H), 7.85 (d, J=9.4 Hz), 7.50 (dd, J=2.8, 9.2 Hz), 7.43-7.37 (m, 1H),7.37-7.25 (m, 1H), 6.54 (d, J=9.4 Hz).

7-Fluoro-1H-quinolin-2-one, (97KK34)

DDQ (0.42 g, 1.9 mmol) was added to a solution of7-fluoro-3,4-dihydro-1H-quinolin-2-one (0.20 g 1.2 mmol) in dioxane (25mL) and the resulting mixture was refluxed under an Argon atmosphere for16 h. The mixture was concentrated under reduced pressure and sataqueous Na₂CO₃ solution (25 mL) was added, and this was extracted withan organic mixture (MeOH/CH₂Cl₂ 1:10, 3×50 mL). The combined organicphase was dried (Na₂SO₄), filtered, concentrated under reduced pressureand purified by combi flash LC (SiO₂; CH₂Cl₂/MeOH 10:1) to give thetitle compound (0.037 g, 18%). ¹H NMR (DMSO-D₆) δ 11.8 (s, 1H), 7.88 (d,J=9.6 Hz, 1H), 7.74-7.65 (m, 1H), 7.05-6.95 (m, 2H), 6.43, (d, J=9.6Hz); ¹³C NMR (CDMSO-D₆) δ 163.0 (d, J=247 Hz), 161.9, 140.4 (d, J=13Hz), 130.4 (d, J=11 Hz), 120.9, 116.1, 109.8 (d, J=23), 101.0 (d, J=25Hz).

6-Fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (10LH75-1) and6-Fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH75-2)

3-Chloro-N-(4-fluoro-3-methyl-phenyl)-propionamide (3.8 g, 30 mmol),3-chloropropionyl chloride (2.9 mL, 30 mmol) and K₂CO₃ (5.0 g, 36 mmol)were added to CH₃CN (50 mL) and the mixture was stirred for 44 h at rt.Thereafter, the reaction was diluted with EtOAc (50 mL) and washed withwater (20 mL), HCl (20 mL, 4N) and brine (20 mL). The organic phase wasdried with Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue (5.9 g) was heated to 135° C. and small portions of AlCl₃ (11 g,82 mmol) were added during 30 min, the reaction was then cooled to 50°C. and HCl (4N 20, mL) was added and the resulting mixture was stirredfor 15 min. The mixture was extracted with EtOAc (50 mL) and the organicphase was washed with water (20 mL). The resulting organic phase wasdried (Na₂SO₄), filtered concentrated under reduced pressure andpurified by prep HPLC to yield6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.76 g, 14%) and6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.190 g, 4%).6-Fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (107LH75-1). ¹H NMR(CDCl₃) δ 8.86 (brs, 8.86, 1H), 6.81 (d, J=9.2 Hz, 1H), 6.62 (d, J=6.8Hz, 1H), 2.91 (brt, J=7.6 Hz, 3H), 2.94-2.87 (m, 2H), 2.20 (d, J=2.0Hz). 6-Fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH75-2). ¹H NMR(CDCl₃) δ 8.78 (brs, 1H), 6.85 (t, J=8.8 Hz, 1H), 6.62 (dd, J=4.5, 8.8Hz, 1H), 2.92 (brt, J=7.6 Hz, 2H), 2.64-2.58 (m, 2H), 2.20 (d, J=2.4 Hz,3H).

(R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM40-37)

A 25 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (0.100 g, 0.670mmol), (S)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesiumcarbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40° C.for 2 days. The reaction mixture was quenched with water (5 mL), and theproduct extracted into EtOAc (2×10 mL). The combined organic layers weredried (Na₂SO₄) and evaporated to give the crude title compound(108LM40-37) (0.219 g).

General Procedure 2 (GP2)

A dry 50 mL flask was charged with the appropriate heterocycle (1.1equiv), (R)-(3-bromo-2-methyl-propoxy)-tert-butyl-dimethylsilane(95MF94) (1 equiv) and cesium carbonate (2.5 equiv) in DMF (20 mL) andstirred at 55° C. for 20 h. The reaction mixture was quenched with water(10 mL), and the product extracted into EtOEt (3×20 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), evaporated andpurified by flash CC (SiO₂; EtOAc/heptane 1:10).

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM24-21)

4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol),(R)-(3-bromo-2-methyl-propoxy)-tert-butyldimethylsilane (95MF94) (4.01g, 15.0 mmol) and Cs₂CO₃ (12.2 g, 37.6 mmol) in DMF (20 mL) were reactedaccording to GP2 to give the title compound (108LM24-21) (3.92 g, 78%).¹H NMR (CDCl₃) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m,2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz,1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz,1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(108LM25-22)

4H-Benzo[1,4]thiazin-3-one (2.75 g, 16.7 mmol),(R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (95MF94) (4.04 g,15.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) in DMF (20 mL) werereacted according to GP2 to give the title compound (108LM25-22) (3.74g, 70%). ¹H NMR (CDCl₃) δ 7.35 (d, J=7.6 Hz, 1H), 7.28-7.18 (m, 2H),6.99 (t, J=7.6 Hz, 1H), 4.13 (dd, J=8.9 Hz, J=13.3 Hz, 1H), 3.95 (dd,J=5.9 Hz, J=13.3 Hz, 1H), 3.52-3.40 (m, 2H), 3.37 (s, CH₂), 1.96-2.07(m, 1H), 0.92-0.83 (m, 12H, 0.02 (s, 6H).

General Procedure 3 (GP3)

A 50 mL flask was charged with the appropriate heterocycle (1 equiv) andtetrabutylammonium fluoride (TBAF) (1.3 equiv) in THF (30 mL) andstirred at rt for 20 h. The reaction mixture was concentrated to syrupand dissolved in EtOAc (30 mL). The mixture was washed with brine (2×20mL). The combined organic layers were dried (Na₂SO₄), evaporated andpurified by flash CC (SiO₂; EtOAc/heptane 7:3).

(S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM26-23)

The compound(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM24-21) (3.92 g, 11.7 mmol) and TBAF (4.78 g, 15.2 mmol) in THF (30mL) were reacted according to GP3 to give the title compound(108LM26-23) (2.52 g, 98%). ¹H NMR (CDCl₃) δ 7.05-6.95 (m, 4H), 4.63 (s,CH₂), 4.23 (dd, J=10.3 Hz, J=13.9 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=13.9Hz, 1H), 3.52-3.49 (m, 1H), 3.46-3.38 (m, 1H), 2.92-2.85 (m, 1H),2.09-1.97 (m, 1H), 1.06 (d, J=7.3 Hz, CH₃).

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one

The compound (108LM25-22) (3.69 g, 10.5 mmol) and TBAF (4.30 g, 13.6mmol) in THF (30 mL) were reacted according to GP3. Purified by flash CC(SiO₂; EtOAc/heptane 7:3) to give the title compound (108LM34-31) (2.36g, 95%). ¹H NMR (CDCl₃) δ 7.38 (d, J=7.9 Hz, 1H), 7.28-7.18 (m, 2H),7.03 (t, J=7.0 Hz, 1H), 4.32 (dd, J=9.0 Hz, J=15.2 Hz, 1H), 3.70 (dd,J=5.5 Hz, J=15.2 Hz, 1H), 3.52 (dd, J=3.4 Hz, J=11.7 Hz, 1H), 3.34-3.42(m, 3H), 2.82 (bs, OH), 1.92-1.83 (m, 1H), 0.98 (d, J=6.9 Hz, CH₃).

General Procedure 4 (GP4)

A 50 mL flask was charged with the appropriate heterocycle (1 equiv),triphenylphosphine (2 equiv) and imidazole (2.5 equiv) in CHCl₃ (30 mL).When all of the material was dissolved iodine (3 equiv) was added whilestirring. Stirring was continued at rt for 20 h. The reaction mixturewas washed with sat. aqueous sodium thiosulfate (30 mL), dried (Na₂SO₄),evaporated and purified by flash CC (SiO2; EtOAc/heptane 3:1).

(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24)

The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM26-23) (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3mmol), imidazole (1.98 g, 29.1 mmol) and iodine (8.88 g, 35.0 mmol) inCHCl₃ (30 mL) were reacted according to GP4 to give the title compound(108LM27-24) (3.02 g, 80%). ¹H NMR (CDCl₃) δ 7.07-7.00 (m, 4H),4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH₂), 3.23-3.14 (m,2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH₃).

(R)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM46-43)

Crude (R)-4-(3-hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM40-37) (1.040 g), triphenylphosphine (0.99 g, 3.77 mmol),imidazole (0.32 g, 4.71 mmol) and iodine (1.43 g, 5.65 mmol) in CHCl₃(30 mL) were reacted according to GP4 to give the crude title compound(108LM46-43) (0.312 g).

(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34)

The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(108LM34-31) (2.33 g, 9.82 mmol), triphenylphosphine (5.15 g, 19.7mmol), imidazole (1.67 g, 24.6 mmol) and iodine (7.48 g, 29.5 mmol) inCHCl₃ (30 mL) were reacted according to GP4 to give the title compound(108LM37-34) (2.57 g, 75%). ¹H NMR (CDCl₃) δ 7.37 (d, J=7.8 Hz, 1H),7.24 (t, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H),4.02 (d, J=6.8 Hz, CH₂), 3.37 (s, CH₂), 3.15-3.05 (m, CH₂), 1.95 (m,1H), 0.97 (d, J=6.2 Hz, CH₃).

General Procedure 5 (GP5)

A 4 or 7 mL vial was charged with 4H-benzo[1,4]oxazin-3-one (1.0 equiv),Cs₂CO₃ (1.5 equiv) and 3-chloro-1-iodopropane (1.1 equiv) in 3 mL dryMeCN and shaken at rt for 66-72 h. The reaction mixture was diluted with10 mL H₂O and extracted into CH₂Cl₂ or EtOAc (3×30 mL). The combinedorganic layers were dried over MgSO₄ or filtered through a PTFF Whatmanfilter and concentrated. The residue was purified by CC (Heptane/EtOAc)or used without further purification in the next step.

6-Bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF50(2084))

6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44) (0.091 g, 0.37mmol), Cs₂CO₃ (0.180 g, 0.55 mmol) and 3-chloro-1-iodopropane (0.083 g,0.41 mmol) were mixed according to GP5. CC (SiO₂; Heptane/EtOAc 9:1-4)gave the title compound (95MF50(2084)) (0.086 g, 72%). ¹H NMR (CDCl₃) d7.02-6.96 (m, 1H), 6.85 (d, J=5.2 Hz, 1H, 4.65 (s, 2H), 4.04-4.11 (m,2H), 3.62 (t, J=6.2 Hz, 2H), 2.10-2.18 (m, 2H); ¹³C NMR (CDCl₃) d 163.8,151.7 (d, J=250.9 Hz), 133.1 (d, J=14.6 Hz), 131.5 (d, J=3.8 Hz), 115.1(d, J=21.5 Hz), 114.2 (d, J=10.0 Hz), 113.4 (d, J=3.4 Hz), 67.6, 42.2,39.5, 30.0.

4-(3-Chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF51(2085))

8-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF45) (0.290 g, 1.74 mmol), Cs₂CO₃(0.848 g, 2.6 mmol) and 3-chloro-1-iodopropane (0.390 g, 1.91 mmol) weremixed according to GP5. CC (SiO₂; Heptane/EtOAc 9:1-4) gave the titlecompound (95MF51(2082)) (0.254 g, 60%). ¹H NMR (CDCl₃) d 7.01-6.95 (m,1H), 6.88-6.82 (m, 2H), 4.66 (s, 2H), 4.13-4.08 (m, 2H), 3.63 (t, J=6.0Hz, 2H), 2.19-2-12 (m, 2H); ¹³ C NMR (CDCl₃) d 164.2, 152.1 (d, J=246.8Hz), 133.9 (d, J=15.0 Hz), 130.6 (d, J=3.1 Hz), 122.6 (d, J=8.1 Hz),111.8 (d, J=18.4 Hz), 110.1 (d, J=3.4 Hz), 67.8, 42.4, 39.5, 30.1.

6,8-Dichloro-4-(3-chloropropyl)-7-ethyl-4H-benzo[1,4]oxazin-3-one((95MF52(2226))

6,8-Dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one (95MF46) (0.342 g, 1.39mmol), Cs₂CO₃ (0.678 g, 2.08 mmol) and 3-chloro-1-iodopropane (0.313 g,1.52 mmol) were mixed according to GP5. CC (SiO₂; Heptane/EtOAc 9:1-4)gave the title compound (95MF52(2226)) (0.301 g, 67%). ¹H NMR (CDCl₃) d7.01 (s, 1H), 4.68 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz,2H), 2.91 (q, J=7.6 Hz, 2H), 2.10-2.18 (m, 2H), 1.16 (t, J=7.6 Hz, 3H);¹³C NMR (CDCl₃) d 163.8, 140.6, 135.8, 127.9, 127.7, 123.6, 113.8, 67.9,42.2, 39.3, 30.0, 24.7, 12.7.

4-(3-Chloropropyl)-8-isopropyl-4H-benzo[1,4]oxazin-3-one (95MF98)

8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83) (0.115 g, 0.60 mmol),Cs₂CO₃ (0.293 g, 0.90 mmol) and 3-chloro-1-iodopropane (0.135 g, 0.66mmol) were mixed according to GP5. CC (SiO₂; Heptane/EtOAc 9:1-4) gavethe title compound (95MF98) (0.112 g, 70%). ¹H NMR (CDCl₃) d 7.03-6.95(m, 2H), 6.93-6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J=6.2Hz, 2H), 3.33-3.25 (m, 1H), 2.20-2.13 (m, 2H), 1.22 (d, J=7.2 Hz, 6H);¹³CNMR (CDCl₃) d 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7,42.5, 39.3, 30.3, 27.2, 22.7.

4-(3-Chloropropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b)

6-Fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol),Cs₂CO₃ (0.263 g, 0.81 mmol) and 3-chloro-1-iodopropane (0.121 g, 0.59mmol) were mixed according to GP5. CC (SiO₂; Heptane/EtOAc 10:1-5) gavethe title compound (8173MF55b) (0.102 g, 78%). ¹HNMR (CDCl₃) d 6.95-6.91(m, 1H), 6.82-6.78 (m, 1H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t,J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); ¹³CNMR (CDCl₃)d 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz),67.8, 42.3, 39.3, 30.0.

4-(3-Chloropropyl)-7,8-difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082b)

7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol),Cs₂CO₃ (0.314 g, 0.96 mmol) and 3-chloro-1-iodopropane (0.144 g, 0.70mmol) were mixed according to GP5 giving the crude title compound (0.156g); ¹H NMR (CDCl₃) d 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H),4.08 (t, J=7.2 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 2.18-2.10 (m, 2H);¹³CNMR (CDCl₃) d 163.5, 147.7 (q, J=245.6 Hz, J=10.4 Hz), 141.0 (q,J=249.4 Hz, J=15.7 Hz), 135.5, 126.2, 109.9 (d, J=18.4 Hz), 108.6 (q,J=7.6 Hz, J=4.2 Hz), 67.8, 42.3, 39.4, 30.0.

4-(3-Chloropropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249b)

6-Methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol),Cs₂CO₃ (0.578 g, 1.77 mmol) and 3-chloro-1-iodopropane (0.265 g, 1.3mmol) were mixed according to GP5. CC (SiO₂; Heptane/EtOAc 10:1-2) gavethe title compound (81MF2249b) (0.127 g, 42%). ¹H NMR (CDCl₃) d 6.88 (d,J=8.8 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.8 Hz,1H), 4.50 (s, 2H), 4.05-4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J=6.2 Hz,2H), 2.16-2.09 (m, 2H); ¹³C NMR (CDCl₃) d 164.8, 155.5, 139.3, 129.2,117.4, 107.8, 101.9, 67.8, 55.8, 42.4, 38.9, 30.0.

4-(3-Chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (81MF763b)

7-Fluoro-4H-benzo[1,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol),Cs₂CO₃ (0.769 g, 2.36 mmol) and 3-chloro-1-iodopropane (0.354 g, 1.73mmol) were mixed according to GP5 giving the crude title compound (0.40g); ¹H NMR (CDCl₃) d 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H),4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H, 2.18-2.11 (m, 2H).

4-(3-Chloropropyl)-4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939b)

4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939a) (0.087 g, 0.52 mmol),Cs₂CO₃ (0.256 g, 0.78 mmol) and 3-chloro-1-iodopropane (0.116 g, 0.57mmol) were mixed according to GP5 giving the crude title compound (0.139g). ¹H NMR (CDCl₃) d 8.43 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.25 (d,J=5.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.41 (s, 2H),2.17-2.10 (m, 2H).

General Procedure 6 (UP6)

A 100 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (1.0 equiv),Cs₂CO₃ (1.5 equiv) and 3-chloro-1-iodopropane (1.1 equiv) in 50 mL dryMeCN and stirred at rt for 72 h. The reaction mixture was evaporated todryness and diluted with 100 mL H₂O and extracted into EtOAc (3×100 mL).The combined organic layers were dried over MgSO₄, filtrated, evaporatedto dryness and purified by CC (Heptane/EtOAc).

6,8-Dichloro-4-(3-chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2225b)

6,8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2225a) (2.33 g,10.0 mmol), Cs₂CO₃ (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25g, 11.0 mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). ¹H NMR(CDCl₃) d 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t,J=6.2, 2H), 2.43 (s, 3H), 2.18-2.10 (m, 2H); ¹³C NMR (CDCl₃) d 163.7,140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.

4-(3-Chloropropyl)-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237b)

6,8-Dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237a) (1.70 g, 9.60 mmol),Cs₂CO₃ (4.69 g, 14.4 mmol) and 3-chloro-1-iodopropane (2.15 g, 10.6mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc 10:1-5) gavethe title compound (81MF2237b) (0.96 g, 39%). ¹H NMR (CDCl₃) d 6.72-6.69(m, 2H), 4.56 (s, 2H), 4.07 (t, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.30 (s,3H), 2.20 (s, 3H), 2.19-2.12 (m, 2H); ¹³C NMR (CDCl₃) d 164.9, 141.5,131.9, 128.0, 126.7, 126.4, 113.1, 67.8, 42.5, 39.0, 30.3, 21.2, 15.5.

6-tert-Butyl-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2248b)

6-tert-Butyl-4H-benzo[1,4]oxazin-3-one (81MF2248a) (2.07 g, 10.0 mmol),Cs₂CO₃ (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc 10:1-5) togive the title compound (81MF2248b) (1.39 g, 49%). ¹H NMR (CDCl₃) d 7.12(d, J=2.0 Hz, 1H), 7.03 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz,1H), 4.54 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H),2.21-2.14 (m, 2H), 1.32 (s, 9H); ¹³C NMR (CDCl₃) d 164.8, 146.4, 143.1,127.9, 120.9, 116.7, 112.2, 67.8, 42.6, 38.9, 34.8, 31.6, 30.2.

6-Chloro-4-(3-chloropropyl)-7-nitro-4H-benzo[1,4]oxazin-3-one(81MF2253b)

Crude 6-Chloro-7-nitro-4H-benzo[1,4]oxazin-3-one (81MF2253a) (2.60 g,10.0 mmol), Cs₂CO₃ (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25g, 11.0 mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc10:1-5) gave the title compound (81MF2253b) (1.23 g, 36%). ¹H NMR(CDCl₃) d 7.66 (s, 1H), 7.20 (s, 1H), 4.70 (s, 2H), 4.12 (t, J=7.6 Hz,2H), 3.67-3.59 (m, 2H), 2.21-2.13 (m, 2H); ¹³C NMR (CDCl₃) d 163.6,143.5, 133.3, 133.2, 122.4, 117.2, 115.2, 67.4, 42.1, 39.6, 29.8.

7-Chloro-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2271b)

7-Chloro-4H-benzo[1,4]oxazin-3-one (81MF2271a) (1.74 g, 9.47 mmol),Cs₂CO₃ (4.63 g, 14.2 mmol) and 3-chloro-1-iodopropane (2.13 g, 10.4mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc 10:1-5) gavethe title compound (81MF2271b) (1.95 g, 79%). ¹H NMR (CDCl₃) d 7.03-6.96(m, 3H), 4.59 (s, 2H), 4.07 (t, J=7.2 Hz, 2H), 3.61 (t, J=6.4 Hz, 2H),2.17-2.10 (m, 2H); ¹³C NMR (CDCl₃) d 164.0, 146.0, 129.1, 127.3, 123.0,117.8, 115.5, 67.7, 42.4, 39.2, 30.0.

4-(3-Chloropropyl)-5-methyl-4H-benzo[1,4]oxazin-3-one (81MF941b)

5-Methyl-4H-benzo[1,4]oxazin-3-one (81MF941a) (1.514 g, 9.28 mmol),Cs₂CO₃ (4.53 g, 13.9 mmol) and 3-chloro-1-iodopropane (2.09 g, 10.21mmol) were mixed according to GP6. CC (SiO₂; Heptane/EtOAc 10:1-5) gavethe title compound (81MF941b) (1.07 g, 48%). ¹H NMR (CDCl₃) d 6.99-6.87(m, 3H), 4.42 (s, 2H), 4.17 (t, J=7.2 Hz, 2 H), 3.45 (t, J=6.4 Hz, 2H),2,41 (s, 3H), 2.04-1.97 (m, 2H); ¹³C NMR (CDCl₃) d 168.3, 149.9, 129.1,128.7, 126.9, 125.1, 115.0, 69.4, 42.2, 42.1, 30.6, 20.9.

4-(3-Chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2246b)

7-Methyl-4H-benzo[1,4]oxazin-3-one (81MF2246a) (1.42 g, 8.7 mmol),Cs₂CO₃ (4.24 g, 13.0 mmol) and 3-chloro-1-iodopropane (1.95 g, 9.5 mmol)were mixed according to GP6. CC (SiO₂; Heptane/EtOAc 10:1-5) gave thetitle compound (81MF2246b) (1.64 g, 79%). ¹H NMR (CDCl₃) d 6.98-6.81 (m,3H), 4.59 (s, 2H), 4.06-4.03 (m, 2H), 3.63-3.60 (m, 2H), 2.26 (s, 2H),2.20-2.15 (m, 2H); ¹³C NMR (CDCl₃) d 164.8, 145.8, 134.3, 123.9, 118.1,114.9, 68.0, 42.8, 39.4, 30.5, 21.0

(R,S)-6-Methyl-4-oxiranylmethyl-4H-benzo[1,4]oxazin-3-one (101IS84F1)

A dry 7 mL vial was charged with 6-methyl-4H-benzo[1,4]oxazin-3-one (160mg, 1.0 mmol), epichlorohydrin (0.147 g, 1.6 mmol), Cs₂CO₃ (0.820 g, 2.5mmol) and dry DMF (1 mL), the mixture was then shaken at 60° C. for 36h. The mixture was diluted with ether (20 mL) washed with water andbrine (10 mL), dried, filtered and concentrated under reduced pressureto give an oil. Purification with flash CC (SiO₂, CH₂Cl₂: acetone/MeOH95:3:2) gave the title compound (0.127 g, 39%). ¹H NMR (CDCl₃) δ 7.01(d, J=1.2 Hz, 1H), 6.84 (d, J=8.4 Hz), 6.80 (dm, J=8.4 Hz), 4.58 (ABqJ=15.2, 21.2 Hz, 2H), 4.50 (dd, J=3.2, 15.2 Hz, 1H), 3.66 (dd, J=6, 15.2Hz), 3.23 (m, 1H), 2.86 (dd, J=4, 4.4 Hz, 1H), 2.69 (dd, J=2.8, 4.8 Hz,1H), 2.33 (s, 3H); ¹³C NMR (CDCl₃) δ 156.2, 143.3, 132.9, 129.0, 124.9,116.9, 116.6, 68.0, 50.2, 25.8, 44.0, 21.3.

General Procedure 7 (GP7)

To a dry 100 mL flask was charged 4H-benzo[1,4]oxazin-3-one (1.0 equiv),(3-bromo-2-methyl-propoxy)-tert-butyldimethylsilane (1.0 equiv), Cs₂CO₃(2.5 equiv) dissolved in dry DMF (40 mL) and stirred under an inertatmosphere at 50° C. for 20-28 hours. To the reaction was added water(100 mL) and extraction using diethyl ether (3×150 mL). The combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄, andconcentrated followed by purification by CC (Heptane/EtOAc)

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(111MF01)

6-Fluoro-4H-benzo[1,4]oxazin-3-one (95MF88) (2.54 g, 15.2 mmol),(R)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.07 g, 15.2 mmol)and Cs₂CO₃ (12.38 g, 38 mmol) were mixed according to GP7. CC (SiO₂;Heptane/EtOAc 9:1) gave the title compound (111MF01) (4.09 g, 76%). ¹HNMR (CDCl₃) d 6.93-6.87 (m, 1H), 6.92-6.88 (m, 1H), 6.68-6.63 (m, 1H),4.56 (m, 2H), 4.01 (m, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H),2.11 (m, 1H), 0.92 (s, 12H), 0.06 (d, J=0.8 Hz, 6H); ¹³C NMR (CDCl₃) d164.8, 158.5 (d, J=239.9 Hz), 141.6 (d, J=2.7 Hz), 130.1 (d, J=10.7 Hz),117.6 (d, J=9.3 Hz), 109.6 (d, J=23.1 Hz), 103.6 (d, J=28.8 Hz), 67.8,65.9, 44.2, 34.5, 26.0, 18.4, 14.9, −5.4, −5.4.

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one111MF14)

7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) (2.52 g, 15.1 mmol),(S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol)and Cs₂CO₃ (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO₂;Heptane/EtOAc 9:1) gave the title compound (111MF14) (3.79 g, 71%). ¹HNMR (CDCl₃) d 7.12 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.67-6.34 (m, 2H), 4.60(q, J=14.8 Hz, J=25.4 Hz, 2H), 4.03 (dd, J=14.0 Hz, 1H), 3.82 (dd, J=5.6Hz, J=14.0 Hz, 1H), 3.57 (dd, J=4.8 Hz, J=10.0 Hz, 1H), 3.45 (dd, J=7.0Hz, J=9.8 Hz, 1H), 2.15-2.05 (m, 1H), 0.93-0.89 (m, 12H), 0.06 (s, 6H);¹³C NMR (CDCl₃) d 164.1, 158.9 (d, J=243.7 Hz), 146.4 (d, J=11.6 Hz),125.3 (d, J=3.0 Hz), 116.4 (d, J=9.6 Hz), 109.1 (d, J=22.7 Hz), 105.1(d, J=25.8 Hz), 67.8, 66.0, 44.1, 34.5, 26.0, 18.4, 14.9, −5.3, −5.4.

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF32)

6-Methoxy-4H-benzo[1,4]oxazin-3-one (111MF24) (2.7 g, 15.1 mmol),(S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol)and Cs₂CO₃ (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO₂;Heptane/EtOAc 9:1) to give the title compound (111MF32) (4.03 g, 80%).¹H NMR (CDCl₃) d 6.89 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.50(dd, J=2.8 Hz, J=8.6 Hz, 1H), 4.53 (q, J=14.8 Hz, J=29.2 Hz, 2H), 3.98(dd, J=8.8 Hz, J=14.0 Hz, 1H), 3.85 (dd, J=5.8 Hz, J=14.2 Hz, 1H), 3.77(s, 3H), 3.57 (dd, J=9.2 Hz, J=10.0 Hz, 1H), 3.47 (dd, J=7.2 Hz, J=10.0Hz, 1H), 2.20-2.12 (m, 1H), 0.91 (s, 12H), 0.05 (d, J=1.2 Hz, 6H); ¹³CNMR (CDCl₃) d 165.3, 155.6, 139.7, 129.8, 117.2, 107.4, 103.3, 68.0,66.2, 55.9, 43.9, 34.3, 26.1, 18.5, 14.7, −5.3, −5.4.

General Procedure 8 (GP8)

To a 100 mL flask was charged4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(1.0 equiv) and Tetrabutylammonium flouride monohydrate (1.3 equiv) anddissolved in 40 mL dry THF. The reaction was stirred in rt under aninert atmosphere for 20-24 hours. The reaction mixture was concentratedand purified by CC (Heptane/EtOAc).

(S)-6-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF03)

The compound(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(111MF01) (4.09 g, 11.6 mmol) and tetrabutylammonium flouridemonohydrate (4.30 g, 15.4 mmol) were mixed according to GP8. CC (SiO₂;Heptane/EtOAc 4:1-4) gave the title compound (111MF03) (2.63 g, 95%). ¹HNMR (CDCl₃) d 6.92 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.80 (dd, J=2.8 Hz,J=10.0 Hz, 1H), 6.71-6.66 (m, 1H), 4.59 (d, J=0.8 Hz, 2H), 4.17-4.11 (m,1H), 3.58-3.40 (m, 3H), 2.79 (s, 1H), 2.08-1.96 (m, 1H) 1.04 (d, J=7.2Hz, 3H); ¹³C NMR (CDCl₃) d 165.3, 158.4 (d, J=238.44 Hz), 141.5 (d,J=2.7 Hz), 129.5 (d, J=10.4 Hz), 117.9 (d, J=9.3 Hz), 110.2 (d, J=23.1Hz), 103.1 (d, J=28.4 Hz), 67.5, 63.85, 43.8, 34.0, 14.9.

(S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF18)

The compound(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methyl-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(111MF14) (3.79 g, 10.7 mmol) and tetrabutylammonium flouridemonohydrate (3.99 g, 14.3 mmol) were mixed according to GP8. CC (SiO₂;Heptane/EtOAc 4:1-4) gave the title compound (111MF18) (2.57 g, 100%).¹H NMR (CDCl₃) d 6.99-6.95 (m, 1H), 7.77-7.72 (m, 2H), 4.63 (m, 2H),4.23-4.16 (m, 1H), 3.58-3.40 (m, 3H), 2.86 (s, 1H), 2.05-1.97 (m, 1H),1.04 (d, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) 164.6, 159.2 (d, J=244.5 Hz),146.4 (d, J=11.6 Hz), 124.9 (d, J=3.1 Hz), 115.9 (d, J=9.6 Hz), 109.4(d, J=22.7 Hz), 105.3 (d, J=26.1 Hz), 67.5, 63.8, 43.8, 34.0, 15.0.

(S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF34)

The compound(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF32) (4.03 g, 12.0 mmol) and tetrabutylammonium flouridemonohydrate (4.46 g, 16.0 mmol) were mixed according to GP8. CC (SiO₂;Heptane/EtOAc 4:1-4) gave the title compound (111MF34) (2.70 g, 100%).¹H NMR (CDCl₃) d 6.91 (d, J=8.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.54(dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.57 (s, 2H), 4.19 (dd, J=9.4 Hz, J=14.6Hz, 1H), 3.78 (s, 3H), 3.56-3.39 (m, 3H), 2.84 (s, 1H), 2.09-1.99 (m,1H), 1.05 (d, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) 165.8, 155.5, 139.5, 129.4,117.4, 107.7, 103.0, 67.7, 63.8, 56.0, 43.6, 34.1, 15.0.

General Procedure 9 (GP9)

A 250 mL flask was charged with4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv)dissolved in CHCl₃ (100 mL). Then triphenylphosphine (2.2 equiv) andimidazole (2.4 equiv) was added. To the solution was added I₂ (2.8equiv) and the reaction was stirred in rt for 15-18 hours. The reactionmixture was quenched with Na₂S₂O₃ (aqueous, sat) (100 mL). The phaseswere separated and the water phase washed with CH₂Cl₂ (150 mL). Thecombined organic layers were dried over Na₂SO₄, concentrated andpurified by CC (Heptane/EtOAc).

(S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF04)

The compound(S)-6-Fluoro-4-(3-hydroxy-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one(111MF03) (2.63 g, 11.0 mmol), triphenylphosphine (6.35 g, 24.2 mmol),imidazole (1.8 g, 26.4 mmol) and I₂ (7.81 g, 30.8 mmol) were mixedaccording to GP9. CC (SiO₂; Heptane/EtOAc 9:1-4) gave the title compound(111MFO4) (3.86 g, 100%). ¹H NMR (CDCl₃) d 6.97-6.93 (m, 1H), 6.82-6.78(m, 1H), 6.73-6.68 (m, 1H), 4.63-4.53 (m, 2H), 3.90 (d, J=6.8 Hz, 2H),3.20-3.16 (m, 2H), 2.15-2.04 (m, 1H), 1.06 (d, J=6.4 Hz, 3H); ¹³C NMR(CDCl₃) d 165.0, 158.5 (d, J=240.2 Hz), 141.7 (d, J=2.3 Hz), 129.6 (d,J=10.4 Hz), 118.1 (d, J=9.2 Hz), 110.1 (d, J=23.4 Hz), 103.1 (d, J=28.7Hz), 67.8, 46.3, 33.5, 18.9, 11.6.

(S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20)

The compound(S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF18) (2.57 g, 11.0 mmol), triphenylphosphine (6.61 g, 23.7 mmol),imidazole (1.76 g, 25.8 mmol) and I₂ (7.64 g, 30.1 mmol) were mixedaccording to GP9. CC (SiO₂; Heptane/EtOAc 9:1-4) gave the title compound(111MF20) (3.31 g, 89%). ¹H NMR (CDCl₃) d 7.00-6.96 (m, 1H), 6.78-6.74(m, 2H), 4.65-4.56 (m, 2H), 3.92 (d, J=7.6 Hz, 2H), 3.21-3.13 (m, 2H),2.13-2.03 (m, 1H), 1.04 (d, J=6.4 Hz, 3H); ¹³C NMR (CDCl₃) d 164.3,159.0 (d, J=244.4 Hz), 146.6 (d, J=12.0 Hz), 125.0 (d, J=3.0 Hz), 115.9(d, J=9.7 Hz), 109.4 (d, J=22.5 Hz), 105.5 (d, J=26.0 Hz), 67.8, 46.3,33.6, 18.9, 11.8.

(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36)

The compound(S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF34) (2.70 g, 12.0 mmol), triphenylphosphine (6.92 g, 26.4 mmol),Imidazole (1.96 g, 28.8 mmol) and I₂ (8.53 g, 33.6 mmol) were mixedaccording to GP9. CC (SiO₂; Heptane/EtOAc 9:1-4) gave the title compound(111MF36) (3.54 g, 82%). ¹H NMR (CDCl₃) d 6.92 (d, J=8.4 Hz, 1H), 6.63(d, J=2.8 Hz, 1H), 6.53 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.54 (q, J=14.8Hz, J=23.6 Hz, 2H), 3.92 (d, J=7.4 Hz, 2H, 3.80 (s, 3H), 3.18 (dd, J=1.0Hz, J=6 Hz, 2H), 2.17-2.08 (m, 1H), 1.05 (d, J=6.8 Hz, 3H); ¹³C NMR(CDCl₃) d 165.4, 155.6, 139.6, 129.4, 117.7, 108.0, 102.5, 68.0, 56.1,46.1, 33.6, 18.9, 12.0.

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS60-1)

A dry 50 mL r-flask was charged with 6-Methyl-4H-benzo[1,4]oxazin-3-one(0.59 g, 3.6 mmol),(R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (1.0 g, 3.6mmol), Cs₂CO₃ (2.9 g, 8.9 mmol) and 10 mL of dry DMF. The mixture wasstirred at 50° C. overnight (15 h) and dissolved in ether (50 mL) washedwith water (20 mL) and the water phase was extracted with ether (20 mL).The combined organic phases were then washed with brine, dried (Na₂SO₄),filtered, concentrated under reduced pressure and the resulting oil waspurified by flash chromatography (SiO₂; Heptane/EtOAc 85:15) to yieldthe title compound as an oil (1.1 g, 88%). ¹H NMR (CDCl₃) δ 6.87 (d,J=1.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.72 (dm, J=8.0 Hz, 1H), 4.5(bars, 2H), 3.93 (dd, J=8.8, 14.0 Hz, 1H), 3.81 (dd, J=5.6, 14.0 Hz,1H), 3.53 (dd, J=4.8, 10.2 Hz, 1H), 3.41 (dd J=7.2, 10.2 Hz, 1H), 2.25(s, 3H), 2.18 (m, 1H), 0.87 (s, 9H), 0.83 (d, J=6.8 Hz, 3H), 0.01 (s,6H); ¹³C NMR (CDCl₃) δ 170.5, 148.9, 137.8, 129.6, 122.2, 121.6, 73.3,71.6, 49.0, 39.7, 31.5, 26.6, 23.8, 20.1, 0.0.

(S)-4-(3-Hydroxy-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS60-2)

The compound(S)-4-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS60-1) (1.0 g, 2.9 mmol) was dissolved in dry THF (12 mL) and TBAF(1.2 g, 3.8 mmol) was added. The reaction was stirred at rt overnightand the solution was concentrated under reduced pressure, the remainingoil was diluted with EtOAc (60 mL) and washed with brine (3×30 mL),dried (Na₂SO₄) filtered and concentrated under reduced pressure. Theremaining oil was purified by flash chromatography (SiO₂; Heptane/EtOAc30:70) to yield an oil which crystallized upon standing (0.69 g, 76%).¹H NMR (CDCl₃) δ 6.88 (d, J=8.4 Hz, 1H), 6.83-6.78 (m, 2H), 4.59 (brs2H, 4.22 (dd, J=10.0, 14.4 Hz), 3.57-3.38 (m, 3H), 2.9 (vbrs, 1H), 2.33(s, 3H), 2.04 (m, 1H), 1.08 (d, J=7.2 Hz); ¹³C NMR (CDCl₃) δ 165.7,143.4, 132.3, 124.9, 117.1, 115.9, 67.6, 63.7, 43.5, 34.2, 21.3, 15.1.

(S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS70)

A dry 50 mL r-flask was charged with(S)-4-(3-hydroxy-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (1.0g, 4.2 mmol), PPh₃ (2.2 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol) anddissolved with CH₂Cl₂ (25 mL). Iodine (2.2 g, 8.4 mmol) was then addedin small portions over 4 h period. After the last addition the reactionwas poured onto SiO₂ and filtered. Concentration under reduced pressureyielded the crude title compound (1.5 g), which was used without furtherpurification.

1-(3-Chloropropyl)-3,4-dihydro-1H-quinolin-2-one (85LM31)

A 50 mL flask was charged with 3,4-dihydro-1H-quinolin-2-one (2.00 g,13.6 mmol) and sodium hydride (60% in oil, 0.712 g, 16.3 mmol) in DMF(50 mL, dry) and stirred at 0° C. for 1 h, followed by addition of1-chloro-3-iodo-propane (2.77 g, 13.6 mmol) and stirring at rt for 20 h.The reaction mixture was quenched with water (10 mL), and the productwas extracted into EtOEt (3×25 mL). The combined organic layers weredried (Na₂SO₄), evaporated and purified by flash CC (SiO₂; EtOAc/heptane1:4) to give the crude title compound (85LM31) (2.25 g). ¹H NMR (CDCl₃)δ 7.29-7.22 (m, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.08-6.98 (m, 2H), 4.10 (t,J=7.3 Hz, CH₂), 3.62 (t, J=5.9 Hz, CH₂), 2.88 (t, J=7.3 Hz, CH₂), 2.63(t, J=7.3 Hz, CH₂), 2.19-2.10 (m, 2H); ¹³C NMR (CDCl₃) δ 170.5, 140.0,128.2, 127.8, 126.3, 123.2, 115.0, 43.3, 40.2, 32.2, 30.5, 26.0.

1-(3-Chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79)

A reaction flask was charged with 6-fluoro-3,4-dihydro-1H-quinolin-2-one(0.180 g, 1.09 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil,0.048 g, 1.20 mmol) was added and the mixture was stirred at rt for 0.5h. Then 1-bromo-3-chloropropane (0.180 g, 1.14 mmol) was added followedby stirring at rt for 20 h. The reaction mixture was quenched withwater, and the product extracted into EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The product waspurified by flash CC (SiO₂; DCM) to give the title compound (92LH79)(0.193 g, 73%). ¹H NMR (CDCl₃) d 7.02-6.88 (m, 3H), 4.09-4.05 (m, 2H),3.61 (t, J=6.3 Hz, CH₂), 2.87 (t, J=6.7 Hz, Ch₂), 2.65-2.61 (m, 2H),2.16-2.09 (m, 2H); ¹³C NMR (CDCl₃) d 169.8, 158.4 (J=242.9 Hz), 135.7(J=2.7 Hz), 128.5 (J=7.7 Hz), 115.7 (J=8.1 Hz), 115.1 (J=22.7), 113.8(J=22.3 Hz), 42.6, 40.3, 31.5, 30.1, 25.5.

(R,S)-1-(3-Chloro-2-methylpropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one(107LH68)

A reaction flask was charged with 6-fluoro-3,4-dihydro-1H-quinolin-2-one(0.496 g, 3.0 mmol) in dry DMF (3 mL) under Argon. NaH (60% in oil,0.132 g, 3.3 mmol) was added and the mixture was stirred at rt for 45min. Then (R,S)-1-bromo-3-chloro-2-methylpropane (0.513 g, 3.0 mmol) wasadded followed by stirring at rt for 20 h. The reaction mixture wasquenched with water, and the product extracted into EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by flash CC (SiO₂; EtOAc/n-heptane 1:1) togive the crude title compound (107LH68) (0.308 g).

1-(3-Chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH 14)

A reaction flask was charged with 6-methyl-3,4-dihydro-1H-quinolin-2-one(107LH05) (0.300 g, 1.26 mmol) in dry DMF (5 mL) under Argon. NaH (60%in oil, 0.055 g, 1.38 mmol) was added and the mixture was stirred at rtfor 1 h. Then 1-bromo-3-chloropropane (0.198 g, 1.24 mmol) was addedfollowed by stirring at rt for 20 h. The reaction mixture was quenchedwith water, and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudeproduct was purified by flash CC (SiO₂; DCM) to give the crude titlecompound (107LH14) (0.257 g).

1-(3-Chloropropyl)-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one(112KK01)

A reaction flask was charged with7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one (97KK40) (0.102 g, 0.57mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.015 g,0.63 mmol) was added and the mixture was stirred at rt for 1 h. Then1-chloro-3-iodopropane (0.104 g, 0.51 mmol) dissolved in DMF (1 mL) wasadded followed by stirring at rt for 20 h. The reaction mixture wasquenched with water, and the product extracted into Et₂O. The combinedorganic layers were washed with aqueous 4% MgSO₄, dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash CC (SiO₂;DCM/n-heptane 2:1, DCM, MeOH/DCM 1:10) to give the title compound(112KK01) (0.050 g, 38%). ¹H NMR (CDCl₃) d 6.95-6.93 (m, 1H), 6.73 (d,J=11.5 Hz, 1H), 4.03-4.00 (m, 2H), 3.59 (t, J=6.5 Hz, CH₂), 2.83-2.79(m, 2H), 2.62-2.58 (m, 2H), 2.20 (d, J=1.8 Hz, CH₃), 2.13-2.07 (m, 2H).

1-(3-Chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (112KK03)

A reaction flask was charged with6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol)in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08mmol) was added and the mixture was stirred at rt for 0.5 h. Then3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) wasadded followed by stirring at rt for 20 h. The reaction mixture wasquenched with water, and the product extracted into Et₂O. The combinedorganic layers were washed with aqueous 4% MgSO₄, dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash CC (SiO₂;DCM) to give the title compound (112KK03) (0.122 g, 47%). ¹H NMR (CD₃OD)d 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH₂), 2.84-2.81(m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H).

1-(3-Chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one and1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one

Neat 2-chloro-N-m-tolylacetamide (92LH85) (1.7 g, 8.5 mmol) was heatedto 135° C. and AlCl₃ (3.4 mg, 26 mmol) was added under an Argonatmosphere, in small portions, during 30 min. The reaction was allowedcool to 60° C. and then HCl (10 mL, 4 M) was added. The mixture wasextracted with EtOAc (2×30 mL) and the combined organic phase was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (SiO₂; CH₂Cl₂/MeOH 9:1) toyield The compound 7-Methyl-3,4-dihydro-1H-quinolin-2-one and5-Methyl-3,4-dihydro-1H-quinolin-2-one (1.1 g). This mixture wasdissolved in dry DMF(8 mL) and NaH (60% in oil, 310 mg, 7.7 mmol) wasadded and the solution was stirred under a N₂ atmosphere at rt for 45min. Thereafter, 1-bromo-3-chloropropan was added and the reaction wasstirred overnight at rt. The reaction mixture was diluted with EtOAc (50mL) and washed with water (10 mL). The organic phase was dried overNa₂SO₄ filtered, concentrated under reduced pressure and the residue waspurified by prep RP-HPLC to yield1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.057 g, 3%)and 1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.12 g,6%). 1-(3-Chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one,(107LH27-11.7). Retention time=11.7 min. ¹H NMR (CD₃OD) δ 7.12 (vbrt,7.7 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.2 Hz, 1H), 4.09-4.02(m, 2H), 3.59 (t, J=6.4 Hz, 2H), 2.85-2.78 (m, 2H), 2.58-2.50 (m, 2H),2.27 (s, 3H), 2.10-2.01 (m, 2H); ¹³C NMR (CD₃OD) δ 171.5, 139.2, 135.9,126.9, 125.4, 125.3, 113.1, 42.2, 40.1, 31.1, 30.3, 21.2, 18.5.1-(3-Chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one,(107LH27-13.1). Retention time=13.1 min. ¹H NMR (CD₃OD) δ 7.02 (brd,J=7.6 Hz, 1H), 6.94 (brs, 1H), 6.81 (brd, J=7.6 Hz, 1H), 4.03 (brt,J=7.2 Hz, 2H), 3.58 (t, J=6.2 Hz, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.51 (t,J=7.4 Hz), 2.30 (s, 3H), 2.09-2.00 (m, 2H); ¹³C NMR (CD₃OD) δ 171.6,139.0, 137.4, 127.8, 123.9, 115.7, 42.3, 39.8, 31.7, 30.3, 24.6, 20.4.

(S)-1-[3-(t-Butyldimethylsilanyl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(122LH 13)

A reaction flask was charged with 3,4-dihydro-1H-quinolin-2-one (1.60 g,10.9 mmol) in dry DMF (30 mL) under Argon. NaH (60% in oil, 0.480 g,12.0 mmol) was added and the mixture was stirred at rt for 1 h. Then(R)-(3-bromo-2-methylpropoxy)-t-butyldimethylsilane (3.0 g, 10.9 mmol)was added followed by stirring at rt for 4 days. The reaction mixturewas quenched with water, and the product extracted into EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash CC (SiO₂; DCM) to givethe title compounds (122LH13) (2.685 g, 74%).

(S)-1-(3-Hydroxy-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH16)

A reaction flask was charged with(S)-1-[3-(t-Butyldimethylsilanyl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(122LH13) (2.685 g, 8.05 mmol) and tetrabutylammonium fluoride (2.70 g,10.3 mmol) in dry THF (20 mL) and stirred at rt for 20 h under an Argonatmosphere. The reaction mixture was concentrated, and the productpurified by flash CC (SiO₂; n-heptane/EtOAc 1:1) to give the titlecompound (122) (1.54 g, 87%).

(S)-1-(3-Iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH 18)

A reaction flask was charged with(S)-1-(3-Hydroxy-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH16)(1.54 g, 7.0 mmol) dissolved in 50 mL DCM. PPh₃ (4.04 g, 15.4 mmol) andimidazole (1.14 g, 16.7 mmol) were added followed by stirring at rt for15 min. The mixture was cooled with an ice-bath followed by addition ofI₂ (5.00 g, 19.7 mmol). The reaction mixture was slowly warmed to rt andstirred over night. The reaction mixture was washed with a Na₂S₂O₃solution, dried over Na₂SO₄, and concentrated. The product was purifiedby flash CC (SiO₂; n-heptane/EtOAc 1:1) to give the title compound(122LH18) (2.140 g, 93%).

1-(3-Chloropropyl)-1H-quinolin-2-one (107LH80).

A 7 mL vial was charged with 1H-quinolin-2-one (0.62 g, 4.2 mmol), 4 mLdry DMF and NaH (60% in oil, 0.200 g, 5.1 mmol). The mixture was stirredunder a N₂ atmosphere at rt for 45 min, and thereafter1-bromo-3-chloropropane (0.42 mL, 4.2 mmol) was added and the reactionwas stirred at rt overnight. The reaction was diluted with EtOAc (50 mL)and washed with water (15 mL). The water phase was extracted with EtOAc(25 mL) and the combined organic phase was dried (Na₂SO₄), filtered,concentrated under reduced pressure and the residue was purified byflash chromatography (SiO₂; CH₂Cl₂) to yield the title compound (0.38 g,41%), containing 15% of 1-(3-bromopropyl)-1H-quinolin-2-one. ¹H NMR(CD₃OD) δ 7.90 (d, J=9.4 Hz, 1H), 7.73-7.57 (m, 3H), 7.34-7.28 (m, 1H),6.66 (d, J=9.4 Hz), 4.46 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H),2.21-2.02 (m, 2H); ¹³C NMR (CD₃OD) δ 163.2, 140.7, 138.8, 131.3, 129.3,122.8, 121.4, 120.2, 114.4, 42.18, 40.2, 30.5.

1-(3-Chloropropyl)-5-metyl-1H-quinolin-2-one, (107LH39).

A microwave vial was charged with1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.081 g, 0.34mmol), DDQ (0.116 g, 0.51 mmol), dioxane (2 mL) and sealed. Aftermicrowave irradiation, 175° C., 10 min, the reaction was diluted withEtOAc (50 mL), washed with sat aqueous NaHCO₃ (2×15 mL) and the organicphase was dried (Na₂SO₄), filtered, concentrated under reduced pressureand the residue was purified with prep RP-HPLC to yield the crude titlecompound (0.053 g), which was used without further purification. HPLC-MS(ammonium acetate) [M+H]⁺=236.2.

1-(3-Chloropropyl)-7-methyl-1H-quinolin-2-one (107LH40)

A microwave vial was charged with1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.88mmol), DDQ (0.30 g, 1.3 mmol), dioxane (4 mL) and sealed. Aftermicrowave irradiation, 175° C., 10 min, the reaction was diluted withEtOAc (50 mL), washed with sat aqueous NaHCO₃ (2×15 mL) and the organicphase was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified with prep RP-HPLC to yield the crudetitle compound (0.130 g), which was used without further purification.HPLC-MS (ammonium acetate) [M+H]⁺=236.2.

(S)-1-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-1H-quinolin-2-one(107LH43)

1H-Quinolin-2-one (1.9 g, 13 mmol) and NaH (60% in oil, 0.58 g, 15 mmol)were added to dry DMF (30 mL) and the reaction was stirred under a N₂atmosphere at rt for 45 min. Thereafter,(R)-(3-bromo-2-methylpropyl)-tert-butyldimethylsilane (3.7 g, 13 mmol)was added and the reaction was stirred for 72 h at 50° C. The reactionwas poured onto water and extracted with EtOAc (2×50 mL) and thecombined organic phase was dried, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂; CH₂Cl₂) to yield the title compound (2.10 g, 6.4 mmol, 48%). ¹HNMR (CDCl₃) δ 7.60-7.53 (m, 2H), 7.49-7.40 (m, 2H), 7.12 (dt, J=0.9, 7.6Hz, 1H), 6.62 (d, J=9.6 Hz, 1H), 4.39 (dd, J=8.4, 14.0 Hz, 1H), 4.15(dd, J=5.4, 14.0 Hz), 3.54 (dd, J=4.4, 10.2 Hz, 1H), 3.45 (dd, J=7.6,10.2 Hz), 2.27-2.12 (m, 1H), 0.88 (s, 12H, 0.01 (s, 6H; ¹³C NMR (CDCl₃)δ 168.2, 145.2, 144.5, 135.8, 134.3, 127.3, 127.2, 126.4, 120.5, 71.7,50.4, 40.9, 31.4, 23.8, 20.4, 0.0.

(S)-1-(3-Hydroxy-2-methylpropyl)-1H-quinolin-2-one (107LH62)

TBAF (1.2 g, 4.6 mmol) and(S)-1-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-1H-quinolin-2-one(0.31 g, 0.93 mmol) were dissolved in THF (5 mL) and stirred under anArgon atmosphere at rt overnight. The mixture was concentrated underreduced pressure and dissolved in EtOAc (30 mL). The solution was washedwith water (15 mL), dried over Na₂SO₄, and concentrated under reducedpressure. The residue thereof was filtered through silica to give thecrude title compound (0.19 g), which was used without furtherpurification.

(S)-1-(3-Iodo-2-methylpropyl)-1H-quinolin-2-one (107LH64)

Imidazole (0.14 g, 2.1 mmol), crude(S)-1-(3-hydroxy-2-methyl-propyl)-1H-quinolin-2-one (0.19 g, 0.87 mmol)and PPh₃ (0.50 g, 1.9 mmol) were dissolved in CH₂Cl₂ (5 mL) and thesolution was cooled to 0° C., thereafter I₂ (0.61 g, 2.4 mmol) was addedand the reaction reached rt overnight. The reaction diluted with CH₂Cl₂(25 mL) and washed with sat aqueous Na₂SO₄ (2×25 mL) and the organicphase was dried over Na₂SO₄, filtered, concentrated under reducedpressure to yield the crude product that was used without furtherpurification. HPLC-MS (ammonium acetate) [M+H]⁺=328.1.

General Procedure 10 (GP10)

A 4 mL vial was charged with the appropriate heterocycle (1 equiv) andthe appropriate piperidine (1.2 or 2 equiv) in dry MeCN (½ mL) andshaken. The reaction mixture was quenched with water (1 mL), and theproduct extracted into EtOAc (2×1 mL). The combined organic layers werepurified by cation exchange CC and by flash CC.

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(108LM43-40)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM37-34) (0.105 g, 0.304 mmol) and 4-butyl-piperidine (0.052 g,0.369 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60°C. for 3 days. Purified by cation exchange CC and flash CC (SiO₂;MeOH/DCM 1:20) to give the title compound (108LM43-40) (0.082 g, 75%).¹H NMR (CDCl₃) δ 7.34 (d, J=9.1 Hz, 1H), 7.25-7.17 (m, 2H), 7.02-6.95(m, 1H), 4.15-3.99 (m, 2H), 3.35 (s, CH₂), 2.83 (bd, J=10.4 Hz, 1H),2.68 (bd, J=10.4 Hz, 1H), 2.20-2.05 (m, 2H), 2.00-1.85 (m, 2H),1.82-1.73 (m, 1H), 1.67-1.55 (m, 2H), 1.30-1.14 (m, 9H), 0.88 (t, J=7.2,CH₃), 0.82 (d, J=6.5 Hz, CH₃); ¹³C NMR (CDCl₃) δ 166.0, 139.2, 128.8,127.1, 124.8, 123.5, 118.9, 63.8, 55.5, 54.4, 47.7, 36.6, 36.1, 32.9,32.8, 32.1, 29.4, 29.3, 23.2, 16.7, 14.4; HPLC-MS (ammonium acetate)[M+H]⁺=361.3.

(R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one(108LM39-46)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM37-34) (0.433 g, 1.25 mmol) and 4-propoxypiperidine (79KS66)(0.225 g, 1.55 mmol) in MeCN (½ mL) were reacted according to GP10shaking at 60° C. for 4 days. Purified by cation exchange CC and flashCC (SiO₂; MeOH/DCM 1:20) to give the title compound (108LM49-46) (0.220g, 49%). ¹H NMR (CDCl₃) δ 7.37 (d, J=8.1 Hz, 1H), 7.25-7.20 (m, 2H),7.05-6.97 (m, 1H), 4.18-4.00 (m, 2H), 3.42-3.35 (m, 4H), 3.30-3.20 (m,1H), 2.80-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.20-2.05 (m, 3H), 2.00-1.82(m, 4H), 1.62-1.50 (m, 4H), 0.92 (t, J=7.4, CH₃), 0.82 (d, J=6.8 Hz,CH₃), ¹³C NMR (CDCl₃) δ 166.1, 139.2, 128.8, 127.1, 124.9, 123.5, 118.8,75.5, 69.8, 63.3, 52.7, 51.9, 47.6, 32.1, 32.0, 29.6, 23.5, 16.6, 10.9;HPLC-MS (ammonium acetate) [M+H]⁺=363.3.

(R)-4-[3-(4-Butylidene-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM50-47)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05)(0.208 g, 1,49 mmol) in MeCN (½ mL) were reacted according to GP10shaking at 60° C. for 4 days. Purified by cation exchange CC and flashCC (SiO₂; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267g, 60%). ¹H NMR (CDCl₃) δ 7.35 (d, J=7.5 Hz, 1H), 7.26-7.18 (m, 2H),6.98 (t, J=7.5 Hz, 1H), 5.10 (t, J=7.4 Hz, CH), 4.17-4.03 (m, 2H), 3.36(s, CH₂), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H),1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); ¹³C NMR (CDCl₃) δ 166.0, 139.2,136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7,36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammoniumacetate) [M+H]⁺=359.3.

(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM51-48)

The compound (S)-4-(3-Iodo-2-methyl-propyl)-4H-benzo[1,4]thiazin-3-one(108LM37-34) (0.093 g, 0.269 mmol) and3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.054 g, 0.323 mmol) inMeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days.Purified by cation exchange CC and flash CC (SiO₂; MeOH/DCM 1:10) togive the title compound (108LM51-48) (0.042 g, 40%). ¹H NMR (CDCl₃) δ7.38 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H),7.00 (t, J=8.0 Hz, 1H), 4.18-4.10 (m, 2H), 3.38 (s, CH₂), 3.15-3.00 (m,2H), 2.30-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.75 (m, 3H), 1.60-1,40(m, 5H), 1,40-1.15 (m, 8H), 0.90-0.82 (m, 6H); ¹³C NMR (CDCl₃) δ 166.1,139.2, 128.7, 127.2, 124.7, 123.5, 119.1, 61,4, 60.1, 57.3, 47.6, 38.3,36.9, 32.1, 31.2, 29.9, 29.4, 28.2, 27.2, 26.5, 23.1, 16.7, 14.3;HPLC-MS (ammonium acetate) [M+H]⁺=387.3.

(R)-4-[2-Methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one(108LM52-49)

The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(108LM37-34) (0.080 g, 0.231 mmol) and3-pentyl-8-azabicyclo[3.2.1]octane (104KS32-2) (0.050 g, 0.276 mmol) inMeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days.Purified by cation exchange CC and flash CC (SiO₂; MeOH/DCM 1:50+1%Et₃N) to give the title compound (108LM52-49) (0.045 g, 49%). ¹H NMR(CDCl₃) δ 7.36 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.6Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 4.16 (d, J=7.3 Hz, CH₂), 3.34 (s, CH₂),3.10-2.95 (m, 2H), 2.25-2.17 (m, 1H), 2.15-2.03 (m, 3H), 1.94-1.75 (m,3H), 1.70-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1,40-1.15 (m, 10H), 0.90-0.80(m, 6H); ¹³C NMR (CDCl₃) δ 166.1, 139.2, 128.7, 127.1, 124.7, 123.4,119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31,4, 29.9, 28.5,28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate)[M+H]⁺=401.3.

General Procedure 11 (GP11)

A 100 mL flask was charged with4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv), K₂CO₃ (2.0equiv), NaI (2.0 equiv) and 4-Butylpiperidine (1.05 equiv) in 25 mL dryMeCN and stirred at rt for 168 h under N₂ atmosphere. The reactionmixture was evaporated to dryness and diluted with 100 mL H₂O andextracted into EtOAc (3×120 mL). The combined organic layers were driedover MgSO₄, evaporated to dryness, and purified by CC (Heptane:EtOAc orCH₂Cl₂:MeOH).

4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2225F)

6,8-Dichloro-4-(3-chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2225b), (2.44 g, 7.92 mmol), K₂CO₃ (2.19 g, 15.84 mmol), NaI (2.37g, 15.84 mmol) and 4-butylpiperidine (1.172 g, 8.3 mmol) were mixedaccording to GP11. CC (SiO₂; Heptane/EtOAc 10:1-4) gave the titlecompound (81MF2225F) (1.55 g, 47%). ¹H NMR (CDCl₃) d 7.11 (s, 1H), 4.65(s, 2H), 3.93 (t, 2H), 2.86, (d, 2H), 2.41 (s, 3H), 2.33 (t, 2H),1.92-1.77 (m, 4H), 1.65 (d, 2H), 1.31-1.19 (m, 9H), 0.88 (t, 3H); ¹³CNMR (CDCl₃) d 163.5, 140.5, 129.9, 128.1, 123.7, 114.0, 67.9, 55.8,54.4, 40.1, 36.4, 36.0, 32.6, 29.2, 24.8, 23.1, 17.2, 14.2.

To the pure compound (0.235 g, 0.50 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.047 g, 0.52 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.24 g, 94%); HPLC-MS (ammonium acetate)[M+H]⁺=413.2

4-[3-(4-Butyl-piperidin-1-yl)propyl]-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one(81MF2237F)

4-(3-Chloropropyl)-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237b)(0.96 g, 3.78 mmol), K₂CO₃ (1.05 g, 7.57 mmol), NaI (1.14 g, 7.57 mmol)and 4-butylpiperidine (0.56 g, 3.97 mmol) were mixed according to GP11.CC (SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF2237F)(0.98 g, 72%). ¹H NMR (CDCl₃) d 6.71 (s, 1H), 6.65 (s, 1H), 4.52 (s,2H), 3.93 (t, J=7.2, 2H), 2.87 (d, J=11.2, 2 H), 2.36 (t, J=7.2 Hz, 2H),2.27 (s, 3H), 2.18 (s, 3H), 1.81-1.89 (m, 4H), 1.65 (d, J=9.6 Hz, 2H),1.28-1.17 (m, 9H), 0.87 (t, J=6-8 Hz, 3H); ¹³C NMR (CDCl₃) d 164.6,141.4, 131.6, 128.3, 126.3, 126.1, 113.4, 67.8, 56.1, 54.3, 39.8, 36.4,35.9, 32.7, 29.1, 25.0, 23.0, 21.1, 15.5, 14.2.

To the pure compound (0.193 g, 0.54 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.051 g, 0.57 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.22 g, 91%); HPLC-MS (ammonium acetate)[M+H]⁺=359.3

6-tert-Butyl-4-[3-(4-butyl-piperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(81MF2248F)

6-tert-Butyl-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2248b)(1.39 g, 4.93 mmol), K₂CO₃ (1.36 g, 9.85 mmol), NaI (1,48 g, 9.85 mmol)and 4-butylpiperidine (0.73 g, 5.17 mmol) were mixed according to GP11.CC (SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF2248F)(1.66 g, 87%). ¹H NMR (CDCl₃) d 7.01-6.98 (m, 2H), 6.91-6.88 (m, 1H),4.55 (s, 2H), 3.99 (t, J=7.2 Hz, 2H), 2.89 (d, J=6.4 Hz, 2H), 2.42 (t,J=6.8 Hz, 2H), 1.92-1.82 (m, 4H), 1.65 (d, J=9.6 Hz 2H), 1.31 (s, 9H),1.29-1.17 (m, 9H), 0.88 (t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 164.6,146.1, 143.3, 128.1, 120.6, 116.6, 112.2, 67.9, 56.5, 54.4, 39.8, 36.4,35.9, 34.7, 32.6, 31.6, 29.2, 24.8, 23.1, 14.2.

To the pure compound (0.178 g, 0.46 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.044 g, 0.49 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.19 g, 87%); HPLC-MS (ammonium acetate)[M+H]⁺=387.4

4-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-4H-benzo[1,4]oxazin-3-one(81MF941x)

4-(3-Chloropropyl)-5-methyl-4H-benzo[1,4]oxazin-3-one (81MF941b) (1.08g, 4.48 mmol), K₂CO₃ (1.24 g, 8.95 mmol), NaI (1.34 g, 8.95 mmol) and4-butylpiperidine (0.66 g, 4.70 mmol) were mixed according to GP11. CC(SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF941x) (0.814g, 53%). ¹H NMR (CDCl₃) d 6.97-6.83 (m, 3H), 4.41 (s, 2H), 4.07 (t,J=7.2 Hz, 2H, 2.67 (d, J=10.8 Hz, 2H), 2.39 (s, 3H), 2.18 (t, J=7.2 Hz,2H, 1.76 (t, J=10.8 Hz, 2H), 1.69-1.62 (m, 2H), 1.58 (d, J=10.0 Hz, 2H,1.30-1.06 (m, 9H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 168.3,150.0, 129.2, 128.9, 126.8, 124.8, 114.8, 69.5, 55.7, 54.2, 42.6, 36.4,35.9, 32.6, 29.2, 25.3, 23.0, 20.9, 14.2.

To the pure compound (0.177 g, 0.52 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.047 g, 0.49 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.21 g, 92%); HPLC-MS (ammoniumacetate) [M+H]⁺=345.1

4-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2246F)

4-(3-Chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2246b) (1.64g, 6.84 mmol), K₂CO₃ (1.89 g, 13.68 mmol), NaI (2.05 g, 13.68 mmol) and4-butylpiperidine (1.02 g, 7.18 mmol) were mixed according to GP11. CC(SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF2246F) (1.85g, 79%). ¹H NMR (CDCl₃) d 6.97 (d, J=8.0 Hz, 1H), 6.82-6.78 (m, 2H),4.54 (s, 2H), 3.94 (t, J=7.2 Hz, 2H), 2.86 (d, J=10.8 Hz, 2H), 2.37 (t,J=7.0 Hz, 2H), 2.28 (s, 3H), 1.92-1.79 (m, 4H), 1.66 (d, J=9.2 Hz, 2H),1.31-1.18 (m, 9H), 0.88 (t, J=7.2 Hz, 3H) ¹³C NMR (CDCl₃) d 164.2,145.3, 133.9, 126.3, 123.3, 117.7, 115.0, 67.8, 56.0, 54.3, 39.7, 36.5,36.0, 32.7, 29.2, 24.9, 23.1, 20.8, 14.2.

To the pure compound (0.156 g, 0.45 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.042 g, 0.47 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.192 g, 97%); HPLC-MS (ammoniumacetate) [M+H]⁺=345.1

4-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-7-nitro-4H-benzo[1,4]oxazin-3-one(81MF2253x)

6-Chloro-4-(3-chloropropyl)-7-nitro-4H-benzo[1,4]oxazin-3-one(81MF2253b) (1.23 g, 4.05 mmol), K₂CO₃ (1.12 g, 8.09 mmol), NaI (1.21 g,8.09 mmol) and 4-butylpiperidine (0.60 g, 4.24 mmol) were mixedaccording to GP11. CC (SiO₂; Heptane/EtOAc 10:1-4) gave the titlecompound (81MF2253x) (0.698 g, 42%). ¹H NMR (CDCl₃) d 7.61 (s, 1H), 7.36(s, 1H), 4.66, (s, 2H), 3.99 (t, J=6.8 Hz, 2H), 2.85 (d, J=11.2 Hz, 2H),2.34 (t, J=6.4 Hz, 2H), 1.94-1.80 (m, 4H), 1.67 (d, J=10.0 Hz, 2H),1.31-1.20 (m, 9H), 0.88 (t, J=6.4 Hz, 3H); ¹³C NMR (CDCl₃) d 163.4,143.4, 141.9, 133.9, 122.1, 117.7, 114.8, 67.5, 55.5, 54.4, 40.5, 36.4,36.0, 32,6, 29.2, 24.6, 23.0, 14.2.

To the pure compound (0.128 g, 0.31 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.029 g, 0.33 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.125 g, 80%); HPLC-MS (ammoniumacetate) [M+H]⁺=410.1

4-[3-(4-Butylpiperidin-1-yl)propyl]-7-chloro-4H-benzo[1,4]oxazin-3-one(81MF2271x)

7-Chloro-4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF2271b) (1.953g, 7.49 mmol), K₂CO₃ (2.07 g, 14.9 mmol), NaI (2.24 g, 14.9 mmol) and4-butylpiperidine (1.11 g, 7.86 mmol) were mixed according to GP11. CC(SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF2271x) (2.46g, 90%). ¹H NMR (CDCl₃) d 7.08-6-96 (m, 3H), 4.57 (s, 2H), 3.95 (t,J=7.2 Hz, 2H), 2.85 (d, J=10.8 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H),1.93-1.78 (m, 4H), 1.66 (d, J=9.2 Hz, 2H), 1.31-1.18 (m, 9H), 0.88 (t,J=6.4 Hz, 3H); ¹³C NMR (CDCl₃) d 163.7, 146.0, 128.7, 127.7, 122.7,117.6, 116.1, 67.7, 55.9, 54.3, 39.9, 36.5, 36.0, 32.7, 29.2, 24.8,23.1, 14.2.

To the pure compound (0.171 g, 0.47 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.043 g, 0.49 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.206 g, 97%); HPLC-MS (ammoniumacetate) [M+H]⁺=365.1

General Procedure 12 (GP12)

A 4 mL vial was charged with4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv), K₂CO₃ (2.0equiv), NaI (2.0 equiv) and amine (1.05 equiv) in 3 mL dry MeCN andshaken at 60° C. for 100 h. The reaction mixture was evaporated todryness, diluted with 4 mL H₂O, extracted into CH₂Cl₂ (3×10 mL), andfiltered through a PTFF Whatman filter. The combined organic layers wereevaporated to dryness and purified by CC (Heptane/EtOAc or CH₂Cl₂/MeOH)or Prep TLC (Heptane/EtOAc or CH₂Cl₂/MeOH).

4-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(8173MF55F)

4-(3-Chloropropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.102g, 0.42 mmol), K₂CO₃ (0.12 g, 0.84 mmol), NaI (0.13 g, 0.84 mmol) and4-butylpiperidine (0.06 g, 0.44 mmol) were mixed according to GP12. CC(SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (8183MF55F) (0.12g, 80%). ¹H NMR (CDCl₃) d. 6.96 (dd, J=10.4 Hz, J=2.8 Hz, 1H), 6.87 (dd,J=9.6 Hz, J=5.2 Hz, 1H), 6.66-6.12 (m, 1H), 4.51 (s, 2H), 3.91 (t, J=7.2Hz, 2H), 2.84 (d, J=11.2 Hz, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.91-1.77 (m,4H), 1.64 (d, J=9.6 Hz, 2H), 1.29-1.16 (m, 9H), 0.86 (t, J=6.8 Hz, 3H);¹³C NMR (CDCl₃) d 164.2, 158.5 (d, J=239.5 Hz), 141,4 (d, J=2.7 Hz),130.0 (d, J=10.4 Hz), 117.5 (J=9.3 Hz), 109.5 (d, J=23.5 Hz), 103.2 (d,J=28.8 Hz), 67.7, 55.7, 54.3, 40.0, 36.4, 35.9, 32.6, 29.1, 24.7, 23.0,14.2.

To the pure compound (0.12 g, 0.34 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.032 g, 0.37 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.128 g, 87%). HPLC-MS (ammoniumacetate) [M+H]⁺=349.2.

4-[3-(4-Butylpiperidin-1-yl)propyl]-7,8-difluoro-4H-benzo[1,4]oxazin-3-one(81MF2082x)

4-(3-Chloropropyl)-7,8-difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082b)(0.16 g, 0.60 mmol), K₂CO₃ (0.17 g, 11.9 mmol), NaI (0.18 g, 11.9 mmol)and 4-butylpiperidine (0.09 g, 0.63 mmol) were mixed according to GP12.CC (SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF2082x)(0.14 g, 65%). ¹H NMR (CDCl₃) d 6.88-6.76 (m, 2H) 4.66 (s, 2H), 3.96 (t,J=7.2 Hz, 2H), 2.84 (d, J=11.2, 2H), 2.34 (t, J=6.8 Hz, 2H), 1.91-1.78(m, 4H), 1.67 (d J=9.6 Hz, 2H), 1.30-1.15 (m, 9H); ^(13C) NMR (CDCl₃) d163.1, 147.4 (q, J=245.0 Hz, J=10.6 Hz), 140.1 (q, J=248.7 Hz, J=15.7Hz), 135.4 (d, J=12.0 Hz), 126.5, 109.5 (d, J=18.4 Hz), 109.0 (q, J=7.6Hz, J=3.8 Hz), 67.8, 55.8, 52,3, 40.1, 36.4, 35.9, 32.7, 29.1, 24.8,23.0, 14.2.

To the pure compound (0.14 g, 0.39 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.042 g, 0.46 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.16 g, 89%). HPLC-MS (ammoniumacetate) [M+H]⁺=367.3.

4-[3-(4-Butylpiperidin-1-yl)propyl]-4H-pyrido[4,3-b][1,4]thiazin-3-one(81MF939)

4-(3-Chloropropyl)-4H-pyrido[4,3-b][1,4]thiazin-3-one (81MF939b) (0.14g, 0.57 mmol), K₂CO₃ (0.16 g, 11.4 mmol), NaI (0.18 g, 11.4 mmol) and4-butylpiperidine (0.09 g, 0.60 mmol) were mixed according to GP12. CC(SiO₂; Heptane/EtOAc 10:1-4) gave the title compound (81MF939) (0.064 g,32%). ¹H NMR (CDCl₃) d 8.48 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.25 (d,J=4.8 Hz, 1H), 4.06-4.12 (m, 2H), 3.41 (s, 2H), 2.82 (d, J=11.2, 2H),2.33 (t, J=6.8 Hz, 2H), 1.83-1.89 (m, 4H), 1.64 (d, J=9.2 Hz, 2H),1.16-1.29 (m, 9H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 163.91,143.84, 138.92, 136.20, 134.04, 122.31, 55.80, 54.32, 43.29, 36.43,35.99, 32.68, 30.78, 29.19, 25.20, 23.05, 14.24.

To the pure compound (0.064 g, 0.18 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.020 g, 0.22 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.16 g, 89%); HPLC-MS (ammoniumacetate) [M+H]⁺=348.2

4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one(81MF07KS)

4-(3-Chloropropyl)-4H-benzo[1,4]thiazin-3-one (81MF07) (0.18 g, 0.74mmol), K₂CO₃ (0.20 g, 14.8 mmol), NaI (0.22 g, 14.8 mmol) and4-propoxypiperidine (0.12 g, 0.81 mmol) were mixed according to GP12. CC(SiO₂; Heptane/EtOAc 4:1-4) gave the title compound (81MF07KS) (0.205 g,79%). ¹H NMR (CDCl₃) d 7.33 (d, J=7.6 Hz, 2H), 7.21 (d, J=3.2 Hz, 2H),7.00-6.96 (m, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.38-3.34 (m, 4H), 3.26-3.21(m, 1H), 2.69 (t, J=5.6 Hz, 2H), 2.33 (t, J=7.2 Hz, 2H), 2.04 (t, J=9.8Hz, 2H), 1.86-1.76 (m, 4H), 1.58-1.51 (m, 4H), 0.90 (t, J=7.2 Hz, 3H);¹³C NMR (CDCl₃) d 165.2, 139.7, 128.5, 127.2, 124.1, 123.4, 118.1, 75.2,69.7, 55.4, 51.5, 43.2, 31.8, 31.7, 25.3, 23.4, 10.8.

To the pure compound (0.205 g, 0.58 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.058 g, 0.64 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.192 g, 74%). HPLC-MS (ammoniumacetate) [M+H]⁺=349.2.

4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(81(81MF08KS)

4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.13 g, 0.58mmol), K₂CO₃ (0.16 g, 1.15 mmol), NaI (0.17 g, 1.15 mmol) and4-propoxypiperidine (0.089 g, 0.60 mmol) were mixed according to GP12.CC (SiO₂; Heptane/EtOAc 4:1-4) gave the title compound (81(81MF08KS))(0.147 g, 76%). ¹H NMR (CDCl₃) d.7.11-7.08 (m, 1H), 7.01-6.94 (m, 3H),4.55 (s, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.37 (t, J=6.8 Hz, 2H), 3.28-3.21(m, 1H), 2.74-2.69 (m, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.10-2.03 (m, 2H),1.90-1.77 (m, 4H), 1.61-1.51 (m, 4H), 0.90 (t, J=7.2 Hz, 3H); ¹³C NMR(CDCl₃) d 164.3, 145.4, 128.7, 123.8, 122.8, 117.1, 115.1, 75.1, 69.6,67.7, 55.5, 51.5, 39.6, 31.6, 24.9, 23.4, 10.7.

To the pure compound (0.147 g, 0.44 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.048 g, 0.53 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.160 g, 86%). HPLC-MS (ammoniumacetate) [M+H]⁺=333.3.

4-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(81MF763)

4-(3-Chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (81MF763b) (0.40g, 1.6 mmol), K₂CO₃ (0.44 g, 3.2 mmol), NaI (0.48 g, 3.2 mmol) and4-butylpiperidine (0.24 g, 1.70 mmol) were mixed according to GP12. CC(SiO₂; Heptane/EtOAc 4:1-4) gave the title compound (81MF763) (0.26 g,46%). ¹H NMR (CDCl₃) d. 7.09-7.04 (m, 1H), 6.74-6.69 (m, 2H), 4.58 (s,2H), 3.95 (t, J=7.2 Hz, 2H), 2.84 (d, J=11.2 Hz, 2H), 3.45 (t, J=6.8 Hz,2H), 1.91-1.78 (m, 4H), 1.66 (d, J=9.2 Hz, 2H), 1.29-1.16 (m, 9H), 0.88(t, 7.2 Hz, 3H); ¹³C NMR (CDCl₃) d 163.6, 158.9 (d, J=243.7 Hz), 146.3(d, J=11.5 Hz), 125.2 (d, J=3.0 Hz), 115.9 (d, J=9.7 Hz), 109.1 (d,J=22.8 Hz), 105.1 (d, J=26.1 Hz), 67.8, 55.9, 54.3, 39.9, 36.5, 36.0,32.7, 29.2, 24.8, 23.1, 14.2.

To the pure compound (0.26 g, 0.74 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.073 g, 0.818 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.26 g, 78%) HPLC-MS (ammoniumacetate) [M+H]⁺=349.3.

4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one(81MF26)

4-(3-Chloropropyl)-4H-benzo[1,4]thiazin-3-one (81MFO7) (0.073 g, 0.30mmol), K₂CO₃ (0.12 g, 0.90 mmol), NaI (0.090 g, 0.6 mmol) and4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according toGP12. Prep TLC (SiO₂; CH₂Cl₂/MeOH 10:1) gave the title compound (81MF26)(0.034 g, 33%). ¹H NMR (CDCl₃) d 7.34-7.31 (m, 1H), 7.23-7.20 (m, 1H),7.00-6.95 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.04 (t, J=7.2 Hz, 2H), 3.34(s, 2H), 2.37-2.32 (m, 6H), 2.23-2.14 (m, 2H), 1.96-1.90 (m, 2H),1.86-1.78 (m, 2H), 1.37-1.27 (m, 2H), 0.86 (t, J=7.2 Hz, 3H); ¹³C NMR(CDCl₃) d 165.1, 139.6, 136.0, 128.5, 127.2, 124.1, 123.4, 122.7, 118.1,55.6, 55.4, 54.8, 43.2, 36.1, 31.7, 29.2, 28.3, 25.2, 23.2, 13.8.

To the pure compound (0.034 g, 0.10 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.010 g, 0.10 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.030 g, 69%); HPLC-MS (ammoniumacetate) [M+H]⁺=345.2

4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(81MF25)

4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.068 g, 0.30mmol), K₂CO₃ (0.12 g, 0.90 mmol), NaI (0.090 g, 0.60 mmol) and4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according toGP12. Prep TLC (SiO₂; CH₂Cl₂/MeOH 10:1) gave the title compound (81MF25)(0.070 g, 71%). ¹H NMR (CDCl₃) d 7.12 (d, J=6.8 Hz, 1H), 7.03-6.95 (m,3H), 5.12 (J=7.4 Hz, 1H), 4.56 (s, 1H), 3.99 (t, J=7.6 Hz, 2H),2.41-2.36 (m, 6H), 2.26-2.17 (m, 2H), 1.98-1.81 (m, 4H), 1.38-1.28 (m,2H), 0.87 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) d 164.3, 145.5, 136.0,128.7, 123.8, 122.8, 122.8, 117.1, 115.2, 67.7, 55.7, 55.6, 54.9, 39.7,36.1, 29.2, 28.4, 24.8, 23.2, 13.8.

To the pure compound (0.070 g, 0.21 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.020 g, 0.22 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.087 g, 97%) HPLC-MS (ammoniumacetate) [M+H]⁺=329.3.

4-[3-(3-Butylidene-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(81MF24)

4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08) (0.030 g, 0.13mmol), K₂CO₃ (0.037 g, 0.26 mmol), NaI (0.040 g, 0.27 mmol) and3-butylidene-8-azabicyclo[3.2.1]octane (0.029 g, 0.17 mmol) were mixedaccording to GP12. Prep TLC (SiO₂; CH₂Cl₂/MeOH 10:1) gave the titlecompound (81MF24) (0.019 g, 41%). ¹H NMR (CDCl₃) d 7.22-7.19 (m, 1H),7.05-6.96 (m, 3H), 5.24 (t, J=7.2 Hz, 1H), 5.08 (s, 2H), 4.06 (t, J=6.4Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.30 (s, 2H), 2.03-1.83 (m, 7H),1.58-1.43 (m, 2H), 1.39-1.22 (m, 3H, 0.89 (m, 3H; ¹³C NMR (CDCl₃) d164.5, 145.5, 131.4, 128.7, 127.9, 124.0, 123.0, 117.1, 115.5, 67.8,60.4, 60.2, 48.8, 41.0, 39.6, 33.7, 29.5, 26.8, 26.4, 25.8, 23.2, 13.9.

To the pure compound (0.019 g, 0.05 mmol) dissolved in diethyl ether (2mL) was added oxalic acid (0.005 g, 0.006 mmol) in diethyl ether (1 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.012 g, 50%); HPLC-MS (ammoniumacetate) [M+H]⁺=355.3

4-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(81MF2249)

4-(3-Chloropropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249b)(0.127 g, 0.50 mmol), K₂CO₃ (0.137 g, 1.0 mmol), NaI (0.149 g, 1.0 mmol)and 4-butylpiperidine (0.075 g, 0.52 mmol) were mixed according to GP12.CC (SiO₂; Heptane/EtOAc 4:1-4) gave the title compound (81MF2249) (0.14g, 85%). ¹H NMR (CDCl₃) d. 6.88 (d, J=8.8 Hz, 1H), 6.67 (d, J=2.4 Hz,1H), 6.49 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 4.51 (s, 2H), 3.93 (t, 7.2 Hz,2H), 3.77 (s, 3H), 2.86 (d, J=10.8 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H),1.90-1.80 (m, 4H), 1.64 (d J=8.8 Hz, 2H), 1.29-1.17 (m, 9H), 0.88 (t,J=6.2 Hz, 3H); ¹³C NMR (CDCl₃) d 168.8, 155.6, 139.6, 129.7, 117.2,107.2, 102.9, 68.0, 56.1, 56.0, 54.4, 39.9, 36.5, 35.9, 32.6, 29.2,24.9, 23.0, 14.2.

To the pure compound (0.14 g, 0.37 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.037 g, 0.41 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.15 g, 90%). HPLC-MS (ammoniumacetate) [M+H]⁺=361.3.

General Procedure 13 (GP13)

A 7 mL vial was charged with4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv), K₂CO₃ (2.0equiv), NaI (2.0 equiv) and 4-Butylpiperidine (1.05 equiv) in 5 mL dryMeCN and shaken at 60° C. for 48 h. The reaction mixture was evaporatedto dryness, diluted with 10 mL H₂O, extracted into CH₂Cl₂ (3×13 mL), andfiltered through a PTFF Whatman filter. The combined organic layers wereevaporated to dryness and purified by CC (Heptane/EtOAc or CH₂Cl₂/MeOH)or prep TLC (Heptane/EtOAc or CH₂Cl₂/MeOH).

4-[3-(4-Butylpiperidin-1-yl)propyl]-6,8-dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one(95MF60)

6,8-Dichloro-4-(3-chloro-propyl)-7-ethyl-4H-benzo[1,4]oxazin-3-one((95MF52(2226)) (0.30 g, 0.93 mmol), K₂CO₃ (0.26 g, 1.86 mmol), NaI(0.28 g, 1.86 mmol) and 4-butylpiperidine (0.14 g, 0.98 mmol) were mixedaccording to GP13. CC (SiO₂; CH₂Cl₂/MeOH 10:0.2-4) gave the titlecompound (95MF60) (0.24 g, 59%). ¹H NMR (CDCl₃) d 7.10 (s, 1H), 4.65 (s,2H), 3.93 (t, J=6.8 Hz, 2H), 2.95-2.81 (m, 4H), 2.33 (t, J=6.8 Hz, 2H),1.90-1.78 (m, 4H), 1.66 (d, J=10.0 Hz, 2H) 1.30-1.13 (m, 12H), 0.88 (s,3H); ¹³C NMR (CDCl₃) d 163.5, 140.6, 135.3, 128.2, 127.7, 123.2, 114.3,67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.7, 29.2, 24.8, 24.6, 23.1, 14.2,12.7; HPLC-MS (ammonium acetate) [M+H]⁺=427.2.

4-[3-(4-Butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF59)

4-(3-Chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF51(2085))(0.25 g, 1.04 mmol), K₂CO₃ (0.29 g, 2.1 mmol), NaI (0.31 g, 2.1 mmol)and 4-butylpiperidine (0.15 g, 1.1 mmol) were mixed according to GP13.CC (SiO₂; CH₂Cl₂/MeOH 10:0.2-4) gave the title compound (95MF59) (0.29g, 80%). ¹H NMR (CDCl₃) d 6.92-6.84 (m, 2H), 6.79-6.74 (m, 1H), 4.59 (s,2H), 3.93 (t, J=7.4 Hz, 2H), 2.81 (d, J=1.08 Hz, 2H), 2.31 (t, J=7.0 Hz,2H), 1.87-1.75 (m, 4H), 1.62 (d, J=9.2 Hz, 2H), 1.27-1.12 (m, 9H), 0.84(t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 163.7, 151.8 (d, J=246.0 Hz), 133.8(d, J=14.6 Hz), 130.7 (d, J=3.5 Hz), 122.1 (d, J=8.0 Hz), 111.2 (d,J=18.4 Hz), 110.4 (d, J=3.4 Hz), 67.6, 55.8, 54.2, 40.0, 36.4, 35.8,32.6, 29.0, 24.8, 22.9, 14.1.

To the pure compound (0.29 g, 0.83 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.078 g, 0.86 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.31 g, 85%). HPLC-MS (ammoniumacetate) [M+H]⁺=349.3.

6-Bromo-4-[3-(4-butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF58)

6-Bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF50(2084)) (0.086 g, 0.27 mmol), K₂CO₃ (0.074 g, 0.53 mmol), NaI(0.080 g, 0.53 mmol) and 4-butylpiperidine (0.039 g, 0.28 mmol) weremixed according to GP13. CC (SiO₂; CH₂Cl₂/MeOH 10:0.2-4) gave the titlecompound (95MF58) (0.040 g, 35%). ¹H NMR (CDCl₃) d 6.92-6.84 (m, 2H),6.79-6.74 (m, 1H), 4.59 (s, 2H), 3.93 (t, J=7.4 hz, 2H), 2.81 (d, J=10.8Hz, 2H), 2.31 (t, J=7.0 Hz, 2H), 1.87-1.75 (m, 4H), 1.62 (d, J=9.2 Hz,2H), 1.27-1.12 (m, 9H), 0.84 (t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 163.7,151.8 (d, J=246.0 Hz), 133.8 (d, J=14.6 Hz), 130.7 (d, J=3.5 Hz), 122.1(d, J=8.0 Hz), 111.2 (d, J=18.4 Hz), 110.4 (d, J=3.4 Hz), 67.6, 55.8,54.2, 40.0, 36.4, 35.8, 32.6, 29.0, 24.8, 22.9, 14.1.

To the pure compound (0.040 g, 0.09 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.009 g, 0.098 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.040 g, 82%). HPLC-MS (ammoniumacetate) [M+H]⁺=427.2.

4-[3-(4-Butylpiperidin-1-yl)propyl]-8-isopropyl-4H-benzol[1,4]oxazin-3-one(111MF02)

4-(3-Chloropropyl)-8-isopropyl-4H-benzo[1,4]oxazin-3-one (95MF98) (0.112g, 0.42 mmol), K₂CO₃ (0.115 g, 0.84 mmol), NaI (0.125 g, 0.84 mmol) and4-butylpiperidine (0.062 g, 0.44 mmol) were mixed according to GP13.Prep TLC (SiO₂; CH₂Cl₂/MeOH 10:1) gave the title compound (111MF02)(0.06 g, 39%). ¹H NMR (CDCl₃) d 6.99-6.91 (m, 3H), 4.55 (s, 2H), 3.96(t, J=7.4 Hz, 2H), 3.27 (m, 1H), 2.89 (d, J=11.2 Hz, 2H), 2.40 (t, J=7.2Hz, 2H), 1.93-1.83 (m, 4H), 1.66 (d, J=9.6 Hz, 2H); 1.27-1.20 (m, 15H),0.88 (t, J=6.8 Hz, 3H); ¹³C NMR (CDCl₃) d 164.7, 142.9, 137.5, 128.7,122.6, 121.1, 112.9, 67.7, 56.0, 54.2, 39.9, 36.4, 35.9, 32.5, 29.1,27.2, 24.9, 23.0, 22.7, 14.2.

To the pure compound (0.06 g, 0.16 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.016 g, 0.18 mmol) in diethyl ether (2 mL).The formed crystals were filtered and washed with diethyl ether to givethe title compound as oxalic salt (0.07 g, 88%). HPLC-MS (ammoniumacetate) [M+H]⁺=373.3.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxy-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS86)

A dry 4 mL vial was charged with(R,S)-6-methyl-4-oxiranylmethyl-4H-benzo[1,4]oxazin-3-one (0.090 g, 0.41mmol), 4-butylpiperidine (0.090 g, 0.60 mmol), K₂CO₃ (0.097 g, 0.70mmol) and dry THF (2 mL). The mixture was shaken at 40° C. for 74 h andwas thereafter concentrated under reduced pressure and the residue wasdiluted with EtOAc (20 mL) and washed with water (10 mL), brine, driedover Na₂SO₄. Filtration, concentration under reduced pressure andpurification of the residue with flash chromatography (SiO₂;CH₂Cl₂/acetone/MeOH 85:10:5) gave the title product as an oil (0.080 g,54%). ¹H NMR (CD₃OD) δ 7.12 (s, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.81 (brd,J=8.2 Hz, 1H), 4.53 (ABq, 14.8, 18.0 Hz, 2H), 4.12-4.02 (m, 2H),3.95-3.85 (m, 1H), 3.05-2.98 (m, 1H), 2,92-2.84 (m, 1H), 2.48-2,40 (m,2H), 2.31 (s, 3H), 2.10-1.98 (m, 2H), 1.71-1.62, (m, 2H), 1.35-1.15 (m,9H), 0.90 (t, J=6.8 Hz). ¹³C NMR (CD₃OD) δ 166.0, 143.7, 132.4, 128.8,124.4, 116.5, 116.4, 67.5, 65.9, 62.8, 54.6, 54.5, 46.1, 36.3, 35.6,32.2 (br), 29.0, 22.8, 20.0, 13.3.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.033g). HPLC-MS (ammonium acetate) [M+H]⁺=361.3.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one(101IS85)

Epichlorohydrin (0.48 g, 5.2 mmol), Cs₂CO₃ (2.3 g, 7.0 mmol),4H-benzo[1,4]oxazin-3-one (0.52 g, 3.5 mmol) were stirred with dry DMF(7 mL) for 22 h. Thereafter the mixture was diluted with ether (50 mL)and washed with water (10 mL) and brine (10 mL). The organic phase wasdried over Na₂SO₄, filtered, concentrated under reduced pressure and theresidue was purified by flash chromatography (SiO₂; CH₂Cl₂/acetone/MeOH95:3:2). The resulting oil (0.50 g, 2.5 mmol) was dissolved in THF,4-butylpiperidine (0.43 g, 3.0 mmol) and K₂CO₃ (0.83 g, 6.0 mmol) wereadded and the reaction was shaken at 40° C. for 72 h. The reaction wasthereafter concentrated under reduced pressure, and the residue waspurified by flash CC (SiO₂; CH₂Cl₂/acetone/MeOH 85:10:5) to give thetitle compound (0.43 g, 1.2 mmol, 35%). ¹H NMR (CD₃OD) δ 7.32 (brd,J=7.2 Hz, 1H), 7.06-6.94 (m, 3H), 4.58 (ABq, J=14.8, 17.6 Hz, 2H),4.13-4.03 (m, 2H), 3.91 (dd, J=8.8, 15.2 Hz), 3.97 (brd, J=10.7 Hz, 1H),2.87 (brd, J=10.1 Hz), 2.43 (d, J=6 Hz, 2H), 2.09-1.96 (m, 2H),1.69-1.60 (m, 2H), 1.34-1.16 (m, 9H), 0.90 (t, J=6.8 Hz); ¹³C NMR(CD₃OD) δ 165.8, 145.8, 129.2, 124.0, 122.6, 116.7, 116.2, 67.4, 65.9,54.7, 54.5, 46.2, 36.3, 35.6, 32.2 (br), 29.0, 22.8, 13.3.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.037g). HPLC-MS (ammonium acetate) [M+H]⁺=347.3.

(−)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one(101IS95)

Following the method outlined above for(R/S)-4-[3-(4-butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-oneusing (R)-(−)-epichlorohydrine (97% ee), (instead of racemicepichlorohydrin, gave the title compound. The optical purity wasdetermined by HPLC analysis (Chiralpak AD, 250×4.6, 5 μm;hexane/i-PrOH/diethylamine 95:4.7:0.3, 0.5 mL/min) to be 96.3% ee.([α]_(D) ²⁰=−6, c=0.5, EtOH).

¹H NMR, ¹³C NMR and HPLC-MS spectral data were identical to those of theracemic compound.

(R,S)-4-[3-(4-Butylpiperidin)-2-methoxypropyl]-4H-benzo[1,4]oxazin-3-one(101IS91)

A dry 4 mL vial was charged with NaH (6.5 mg, 0.15 mmol) and then asolution of(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one(101IS85) (0.043 g, 0.12 mmol) in dry THF (1 mL) was added and themixture was allowed to stir at rt for 2 h. Thereafter, neat MeI (7.5 μl,0.12 mmol) was added and after another 2 h at rt the reaction mixturewas quenched with water (2 mL) and extracted with EtOAc (3×10 mL). Theorganic phase was dried over Na₂SO₄, filtered, concentrated underreduced pressure and the residue was purified by flash chromatography(SiO₂; CH₂Cl₂/acetone/MeOH 90:6:4) to yield the title compound as an oil(5.1 mg, 12%). ¹H NMR (CD₃OD) δ 7.25 (dm, J=7.2 Hz, 1H), 7.00-6.88 (m,3H), 4.49 (ABq, J=15.2, 18.8 Hz, 2H), 4.06-3.94 (m, 2H), 3.69-3.61 (m,1H), 3.25 (s, 3H), 2.94-2.82 (m, 2H), 2.54-2.36 (m, 2H), 2.10-1.94 (m,2H), 1.64-1.55 (m, 2H), 1.25-1.05 (m, 9H), 0.81 (t, J=6.8 Hz); ¹³C NMR(CD₃OD) δ 165.9, 146.0, 129.1, 124.2, 122.7, 116.8, 116.1, 76.0, 67.5,60.2, 57.2, 54.6, 54.5, 43.7, 36.2, 35.3, 31.8, 28.9, 22.8, 13.2;HPLC-MS (ammonium acetate) [M+H]⁺=361.3.

(R,S)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(123IS03)

Epichlorohydrin (0.48 g, 5.2 mmol), Cs₂CO₃ (2.3 g, 7.0 mmol),4H-benzo[1,4]oxazin-3-one (0.52 g, 3.5 mmol) were stirred with dry DMF(7 mL) for 22 h. Thereafter the mixture was diluted with ether (50 mL)washed with water (10 mL) and then brine (10 mL). The organic phase wasdried over Na₂SO₄, filtered, concentrated under reduced pressure and theresidue was purified by flash CC (SiO₂; CH₂Cl₂/acetone/MeOH 95:3:2). Ofthe resulting oil (0.060 g, 0.29 mmol) was dissolved in DMF (1.5 mL),3-pentyl-8-azabicyclo[3.2.1]octane (0.060 g, 0.33 mmol) and Cs₂CO₃ (0.30g, 0.81 mmol) were added and the mixture was shaken at 65° C. for 72 h.The mixture was then poured into ether (25 mL) washed with water (10 mL)and the water phase was extracted with ether (20 mL). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered, concentrated under reduced pressure and the residue waspurified by cation exchange CC, followed by flash CC (SiO₂;CH₂Cl₂:acetone:MeOH 85/10/5) to yield the title compound (0.060 g, 33%(from 4H-benzo[1,4]oxazin-3-one)). ¹H NMR (CDCl₃) δ 7.42 (dm, J=7.2 Hz,1H), 7.05-6.94 (m, 3H), 4.60 (ABq, J=14.8, 16.8 Hz, 2H), 4.15 (dd,J=3.2, 14.0 Hz, 1H), 3.86-3.78 (m, 3H), 3.14 (m, 2H), 2.54 (dd, J=4.8,12.5 Hz, 1H), 2.22 (dd, J=9.2, 12.4 Hz), 2.16-1.98 (m, 2H), 1.98-1.83(m, 2H), 1.72-1.55 (m, 3H), 1.43-1.34 (m, 2H), 1.42-1.15 (m, 8H), 0.87(t, J=7.2 Hz). ¹³C NMR (CDCl₃) δ 165.3, 145.5, 129.7, 124.2, 122.9,117.0, 116.6, 67.9, 67.4, 60.9, 58.6, 56.7, 46.7, 38.3, 36.7, 36.5,28.5, 28.3, 28.2, 27.1, 22.9, 14.3. HPLC-MS (ammonium acetate)[M+H]⁺=387.3.

4-[2-(4-Butylpiperidin-1-ylmethyl)allyl]-4H-benzo[1,4]oxazin-3-one(123IS02)

3-Chloro-2-chloromethyl-1-propene (0.20 g, 1.5 mmol),4H-benzo[1,4]oxazin-3-one (0.15 g, 1.0 mmol) and Cs₂CO₃ (0.65 g, 2.0mmol) were mixed with 1 mL DMF and were shaken at 65° C. for 5 h. Themixture was diluted with ether (20 mL) and washed with water (20 mL) andthe water phase was extracted with ether (20 mL). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filteredconcentrated under reduced pressure and the residue was purified byflash CC (SiO₂; heptane/EtOAc 70:30). This product (0.080 g, 0.34 mmol)was dissolved in DMF (1 mL), thereafter 4-butylpiperidine (0.053 g, 0.37mmol) and Cs₂CO₃ (0.23 g, 0.71 mmol) were added and the mixture wasshaken at 65° C. for 24 h. The mixture was then poured into ether (25mL) washed with water (10 mL) and the water phase was extracted withether (20 mL). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered, concentrated under reduced pressure and theresidue was purified by cation exchange CC, followed by flash CC (SiO₂;EtOAc/MeOH/NH₄OH (25% NH₃ in water) 97.5:2:0.5), to yield the titlecompound (0.075 g, 21%). ¹H NMR (CDCl₃) δ 7.05-2.92 (m, 4H), 5.01 (brs,1H), 4.82 (brs, 1H), 4.64 (brs 2H), 4.57 (brs, 2H), 2.94 (brs, 2H), 2.86(brd, J=10.4 Hz, 2H), 1.93-1.82 (m, 2H), 1.71-1.62 (m, 2H), 1.34-1.15(m, 9H), 0.89 (t, J=6.2 Hz, 3H); ¹³C NMR (CDCl₃) δ 1.64.5, 145.4, 129.2,123.9, 122.8, 116.9, 113.2, 67.9, 63.2, 54.4, 44.8, 36.6, 36.0, 32.8,29.3, 23.1, 14.3; HPLC-MS (ammonium acetate) [M+H]⁺=343.3.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-fluoropropyl]-4H-benzo[1,4]oxazin-3-one(101IS96)

A 4 mL vial was charged with(R,S)-4-butyl-1-(3-chloro-2-fluoropropyl)piperidine (0.020 g, 85 μmol)and 4H-benzo[1,4]oxazin-3-one (0.023 g 0.16 mmol) and CH₃CN (1 mL). Themixture was stirred at 60° C. for 70 h and the mixture was diluted withMeOH and filtered through a small silica pad onto a cationic-exchangeCC. Concentration under reduced pressure yielded an oil that waspurified by flash chromatography (SiO₂; heptane:EtOAc 50/50;) to yieldthe title compound as an oil (0.011 g, 38%). ¹H NMR (CD₃OD) δ 7.28-7.24(m, 1H), 7.07-6.96 (m, 3H), 5.05 (dm, J=50.4 Hz), (ABq, J=15.2, 20.oHz), 4.29-4.12 (m, 2H), 3.00-2.92 (m, 2H), 2.78-2.60 (m, 2H), 2.14-2.05(m, 2H), 1.73-1.63 (m, 2H), 1.35-1.16 (m, 10H), 0.90 (t, J=6.8 Hz, 3H).¹³C NMR (CD₃OD) δ 165.8, 145.8, 129,0, 124.2, 122.7, 116.8, 117.0,116.8, 89.5 (d, J=174 Hz), 67.4, 60.1 (d, J=21 Hz), 54.5, 43.8 (d, J=23Hz), 36.2, 35.4, 32.0, 31.9, 28.9, 22.8, 13.2.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.037g). HPLC-MS (ammonium acetate) [M+H]⁺=349.3.

(S)-4-[3-(4-Butyl-piperidin-1-yl)-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(108LM53-50)

A 4 ml vial was charged with crude(R)-4-(3-iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM46-43)(0.312 g) and 4-butyl-piperidine (0.210 g, 1.49 mmol) in dry MeCN (½ ml)and shaken at 60° C. for 3 days. The reaction mixture was quenched withwater (1 ml), and the product extracted into EtOAc (2×1 ml). Thecombined organic layers were added a cation exchange column. The columnwas washed with MeOH (2 column volumes) then the product was eluded ofthe column using 8% ammonium hydroxide in MeOH (2 column volumes). Theproduct was purified by flash CC (SiO₂; MeOH/DCM 1:20) to give the titlecompound (108LM53-50) (0.193 g, 17% -3 steps). ¹H NMR (CDCl₃) δ 7.18 (d,J=7.8 Hz, 1H), 7.03-6.96 (m, 3H), 4.58 (ABq, J=14.3 Hz, J=33.9 Hz, CH₂),4.05-3.90 (m, 2H), 2.88 (bd, J=10.4 Hz, 1H), 2.71 (bd, J=10.4 Hz, 1H),2.25-2.01 (m, 3H), 2.00-1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.68-1.56 (m,2H), 1.33-112 (m, 9H), 0.95-0.85 (m, 6H); ¹³C NMR (CDCl₃) δ 164.9,145.7, 128.9, 123.8, 122.7, 117.2, 115.8, 67.8, 64.2, 55.8, 54.4, 45.4,36.6, 36.1, 33.0, 32.8, 29.3, 23.2, 17.1, 14.4; HPLC-MS (ammoniumacetate) [M+H]⁺=345.3.

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM22-20)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24) (0.063 g, 0.19 mmol) and 4-butyl-piperidine (0.053 g, 0.38mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 50° C.for 1 day and at 70° C. for 2 days. Purified by cation exchange CC andflash CC (SiO₂; MeOH/DCM 1:50) to give the title compound (108LM22-20)(0.051 g, 79%). ¹H NMR (CDCl₃) δ 7.18-7.15 (m, 1H), 7.02-6.96 (m, 3H),4.60 (ABq, J=15.0 Hz, J=31.3 Hz, CH₂), 3.99 (dd, J=8.1 Hz, 13.8 Hz, 1H),3.92 (dd, J=5.0 Hz, 13.8 Hz, 1H), 2.88 (bd, J=10.0 Hz, 1H), 2.72 (bd,J=10.0 Hz, 1H), 2.26-2.02 (m, 3H), 2.00-1.92 (m, 1H), 1.85-1.75 (m, 1H),1.70-1.59 (m, 2H), 1.32-1.14 (m, 9H), 0.92-0.85 (m, 6H); HPLC-MS(ammonium acetate) [M+H]⁺=345.3.

General Procedure 14 (GP14)

A 4 mL vial was charged with the appropriate heterocycle (1 equiv) andthe appropriate piperidine (1.1 equiv) and shaken at 60° C. for 2 days.Et₃N (½ mL) was added and shaking was continued for 1 day. The reactionmixture was quenched with water (1 mL), and Et₂O (1 mL) and sodiumhydroxide (until pH 10) were added. The product was extracted into Et₂O(2×1 mL). The combined organic layers were dried over Na₂SO₄, andconcentrated. The product was purified by cation exchange CC followed byflash CC (Si₂O; MeOH/DCM 1:50).

(R)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(108LM32-29)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24) (0.202 g, 0.61 mmol) and 4-propoxy-piperidine (79KS66)(0.097 g, 0.67 mmol) in MeCN (½ mL) were reacted according to GP14 togive the title compound (108LM32-29) (0.136 g, 65%). ¹H NMR (CDCl₃) δ7.15 (bd, J=7.3 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=13.9 Hz, J=31.6Hz, CH₂), 4.05-3.90 (m, 2H), 3.48 (t, J=7.0 Hz, CH₂), 3.28-3.20 (m, 1H),2.79 (bs, 1H), 2.63 (bs, 1H), 2.27-2.11 (m, 3H), 2.10-1.93 (m, 2H),1.92-1.83 (m, 2H), 1.63-1.52 (m, 4H), 0.94-0.86 (m, 6H); 13C NMR (CDCl3)δ 164.5, 145.4, 128.5, 123.4, 122.3, 116.9, 115.2, 75.0, 69.4, 67.4,63.2, 52.5, 51.5, 45.0, 31.6, 31.5, 29.1, 23.1, 16.6, 10.5; HPLC-MS(ammonium acetate) [M+H]⁺=347.3.

(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM33-30)

The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24) (0.441 g, 1.33 mmol) and 4-butylidenepiperidine (111MF05)(0.204 g, 1.47 mmol) in MeCN (½mL) were reacted according to GP14 togive the title compound (108LM33-30) (0.293 g, 64%). ¹H NMR (CDCl₃) δ7.19 (bd, J=7.0 Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J=7.9 Hz, CH), 4.60(ABq, J=14.1 Hz, J=16.2 Hz, CH₂), 4.00 (d, J=7.0 Hz, CH₂), 2.50-2.38 (m,2H), 2.35-2.05 (m, 9H), 1.95 (dt, J=7.0 Hz, CH₂), 1.50-1.40 (m, 2H),0.94-0.86 (m, 6H); ¹³C NMR (CDCl₃) δ 165.0, 145.8, 136.3, 128.9, 123.8,122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4,28.6, 23.4, 17.1, 13.9; HPLC-MS (ammonium acetate) [M+H]⁺=343.3.

General Procedure 15 (GP15)

A 7 mL vial was charged with the appropriate heterocycle (1 equiv) andthe appropriate piperidine (1.1 equiv) in Et₃N (½mL) and shaken at 60°C. for 4 days. The reaction mixture was quenched with water (1 mL), andEt₂O (1 mL) and sodium hydroxide (until pH 10) were added. The productwas extracted into Et₂O (10×1 mL) and EtOAc (10×1 mL). The combinedorganic layers were dried (Na₂SO₄), and concentrated. The product waspurified by cation exchange CC followed by flash CC (Si₂O; MeOH/DCM1:20).

(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM38-35)

The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24) (0.092 g, 0.28 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane(104KS29) (0.051 g, 0.31 mmol) in Et₃N (½ mL) were reacted according toGP15 to give the title compound (108LM38-35) (0.068 g, 64%). ¹H NMR(CDCl₃) δ 7.32 (d, J=6.7 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=7.2Hz, J=10.8 Hz, CH₂), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H),2.33 (dd, J=6.1 Hz, J=2.1 Hz, 1H), 2.12 (t, J=4.7 Hz, 1H), 2.01-1.78 (m,2H), 1.58-1.40 (m, 5H), 1.38-1.13 (m, 9H), 0.92-0.84 (m, 6H); ¹³C NMR(CDCl₃) δ 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8,60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1,17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]⁺=371.3.

(R)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one(108LM39-36)

The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24) (0.083 g, 0.25 mmol) and3-pentyl-8-aza-bicyclo[3.2.1]octane (104KS32-2) (0.051 g, 0.28 mmol) inEt₃N (½ mL) were reacted according to GP15 to give the title compound(108LM39-36) (0.061 g, 63%). ¹H NMR (CDCl₃) δ 7.33-7.29 (m, 1H),7.03-6.96 (m, 3H), 4.60 (ABq, J=14.8 Hz, J=37.1 Hz, CH₂), 4.14-4.00 (m,2H), 3.13 (bs, 1H), 3.05 (bs, 1H), 2.63-2.50 (m, 1H), 2.17-2.03 (m, 3H),2.00-1.80 (m, 3H), 3H), 1.42-1.15 (m, 10H), 0.93-0.85 (m, 6H); ¹³C NMR(CDCl₃) δ 165.0, 145.7, 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9,58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9,17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]⁺=385.3.

General Procedure 16 (GP16)

A 7 mL vial charged with4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv) andamine (1.0 equiv) was shaken at 60° C. for 20 hours. The reactionmixture was added Et₃N (2.5 equiv) and shaken at 60° C. for 60-80 hours.The reaction mixture was concentrated, dissolved in 1 M NaOH (10 mL),extracted into CH₂Cl₂ (3×15 mL), and dried through a PTFF Whatmanfilter. The combined organic layers were concentrated and purified bycation exchange CC and CC (Heptane/EtOAc) or Prep HPLC.

(R)-6-Fluoro-4-[2-methyl-3-(4-propoxy-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(108LM30-27)

The compound(S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one(111MF04) (0.400 g, 1.15 mmol) and 4-propoxy-piperidine (79KS66) (0.332g, 2.29 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at60° C. for 3 days and at 70° C. for 1 day. Purified by cation exchangeCC and flash CC (SiO₂; MeOH/DCM 1:50→1:20) to give the title compound(108LM30-27) (0.263 g, 63%). ¹H NMR (CDCl₃) δ 6.96 (dd, J=9.7 Hz, J=2.9Hz, 1H), 6.91 (dd, J=8.9 Hz, J=4.9 Hz, 1H), 6.66 (dt, J=8.9 Hz, J=2.9Hz, 1H), 4.56 (ABq, J=15.5 Hz, J=31.7 Hz, CH₂), 3.95 (dd, J=13.5 Hz,J=8.1 Hz, 1H), 3.88 (dd, J=13.5 Hz, J=4.7 Hz, 1H), 3.38 (t, J=6.7 Hz,CH₂), 3.32-3.23 (m, 1H), 2.79 (bs, 1H), 2.62 (bs, 1H), 2.26-2.12 (m,3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85(m, 6H); ¹³C NMR (CDCl₃) δ 164.9, 158.5 (d, J=952.8 Hz, 1H), 141.7 (d,J=9.2 Hz, 1H), 130.0 (d, J=42.4 Hz, 1H), 117.7 (d, J=38.4 Hz, 1H), 109.6(d, J=93.2 Hz, 1H), 103.4 (d, J=114.4 Hz, 1H), 75.2, 69.8, 67.9, 63.7,52.8, 52.0, 45.7, 31.8, 31.6, 29.5, 23.5, 17.1, 10.9; HPLC-MS (ammoniumacetate) [M+H]⁺=365.3.

(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methyl-propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(111MF06)

The compound(S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one(111MF04)_(0.718 g, 2.06 mmol) and 4-Butylidenepiperidine (0.301 g, 2.16mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF06) (0.40 g, 54%). ¹HNMR (CDCl₃) d 7.01 (dd,J=3.0 Hz, J=10.2 Hz, 1H), 6.90 (dd, J=5.4 Hz, J=8.6 Hz, 1H), 6.89-6.63(m, 1H), 5.12 (t, J=7.4 Hz, 1H), 4.63-4.51 (m, 2H), 4.02-3.89 (m, 1H),2.51-2.44 (m, 2H), 2.32-2.23 (m, 5H), 2.21-2.15 (m, 5H), 2.11-2.03 (m,1H), 1.98-1.93 (m, 2H), 1.39-1.29 (m, 2H), 0.91-0.86 (m, 6H); ¹³C NMR(CDCl₃) d 164.8, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.7 Hz), 136.2,130.0 (d, J=10.8 Hz), 122.7, 117.6 (d, J=9.3 Hz), 109.5 (d, J=23.1 Hz),103.4 (d, J=29.1 Hz), 67.8, 63.7, 56.6, 55.8, 45.7, 36.2, 29.4, 29.3,28.4, 23.3, 17.0, 13.9.

To the pure compound (0.38 g, 1.0 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.104 g, 1.15 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.44 g, 92%); HPLC-MS (ammonium acetate)[M+H]⁺=361.4

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(111MF08)

The compound(S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one(111MF04)_(0.873 g, 2.50 mmol) and 4-Butylpiperidine (0.371 g, 2.63mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF08) (0.53 g, 58%). ¹H NMR (CDCl₃) d 7.01 (d,J=10.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.68-6.64 (m, 1H), 5.57 (q, J=32.4Hz, J=15.2 Hz, 2H), 4.02-3.83 (m, 2H), 2.92-2.70 (m, 2H), 2.23-2.10 (m,2H), 2.04-1.97 (m, 2H), 1.81 (t, J=10.8 Hz, 1H), 1.72-1.61 (m, 2H),1.36-1.19 (m, 9H), 0.90-0.88 (m, 6H); ¹³C NMR (CDCl₃) d 164.8, 158.5 (d,J=239.4 Hz), 141.6 (d, J=2.3 Hz), 130.0 (d, J=10.4 Hz), 117.6 (d, J=9.6Hz), 109.4 (d, J=23.1 Hz), 103.5 (d, J=29.3 Hz), 67.8, 64.1, 56.0, 54.3,45.7, 36.5, 36.0, 33.0, 32.5, 29.5, 29.2, 23.1, 17.1, 14.3.

To the pure compound (0.53 g, 1.5 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.104 g, 1.15 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.614 g, 93%); HPLC-MS (ammonium acetate)[M+H]⁺=363.3.

(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(111MF26)

The compound(S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[1,4]oxazin-3-one(111MF04) (0.219 g, 0.6 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane(0.10 g, 0.6 mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc(4:1-4) gave the title compound (111MF26) (0.16 g, 58%). ¹H NMR (CDCl₃)d 7.16 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.0 Hz, J=9.0 Hz, 1H),6.69-6.63 (m, 1H), 4.58 (q, J=14.8 Hz, J=38.0 Hz, 2H), 4.10-3.93 (m,2H), 3.16-3.06 (m, 2H), 2.33 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.05 (t,J=11.6 Hz, 1H), 1.94-1.82 (m, 2H), 1.58-1.43 (m, 6H), 1.39-1.32 (m, 2H),1.31-1.15 (m, 6H), 0.90-0.87 (m, 6H); ¹³C NMR (CDCl₃) d 164.9, 158.5 (d,J=239.4 Hz), 141.6 (d, J=2.7 Hz), 130.0 (d, J=10.4 Hz), 117.5 (d, J=9.3Hz), 109.4 (d, J=23.5 Hz), 103.9 (d, J=28.9 Hz), 67.8, 61.9, 60.1, 58.2,45.6, 38.6, 38.5, 36.9, 31.8, 29.4, 28.2, 27.4, 26.5, 23,1, 17.1, 14.3.

To the pure compound (0.16 g, 0.41 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.039 g, 0.43 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.173 g, 88%); HPLC-MS (ammonium acetate)[M+H]⁺=389.3

(R)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(111MF27)

The compound(S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF04)_(—()0.208 g, 0.6 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane(0.10 g, 0.56 mmol) were mixed according to GP16. CC (SiO₂;Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). ¹HNMR (CDCl₃) d 7.13 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.2 Hz,J=8.8 Hz, 1H), 6.68-6.63 (m, 1H), 4.57 (q, J=14.8 Hz, J=40.0 Hz, 1H),4.11-3.94 (m, 2H), 3.14-3.04 (m, 2H), 2.30 (dd, J=4.0 Hz, J=12.8 Hz,1H), 2.20-2.09 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 3H), 1.71-1.52(m, 3H), 1.40-1.34 (m, 2H), 1.32-1.19 (m, 8H), 0.89-0.8 (m, 6H); ¹³C NMR(CDCl₃) d 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.6 Hz), 130.0 (d,J=10.8 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.4 Hz), 103.8 (d, J=28.9Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4,28.4, 28.2, 27.2, 22.8, 7.0, 14.2.

To the pure compound (0.16 g, 0.41 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.039 g, 0.43 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.198 g, 97%); HPLC-MS (ammonium acetate)[M+H]⁺=403.3

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-7-Fluoro-4H-benzo[1,4]oxazin-3-one(112KK04)

A microwave vial was charged with(S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20) (0.274 g, 0.78 mmol) and 4-butylpiperidine (0.226 g, 1.60mmol) in MeCN (4 mL) and sealed. After microwave irradiation, 100° C.,60 min, the reaction mixture was purified by cation exchange CC followedby flash CC (SiO₂; CH₂Cl₂/MeOH 50:1) to give the title compound(112KK04) (0.180 g, 63%). ¹H NMR (CD₃OD) d 7.24-7.21 (m, 1H), 6.81-6.76(m, 2H), 4.60 (ABq, J=17.4 Hz, J=15.1 Hz, CH₂), 3.98 (dd, J=14.3 Hz,J=5.9 Hz, 1H), 3.87 (dd, J=14.3 Hz, J=7.6 Hz, 1H), 2.86 (d, J=11.0 Hz,1H), 2.73 (d, J=9.8 Hz, 1H), 2.28-2.23 (m, 1H), 2.16-2.08 (m, 2H),1.93-1.81 (m, 2H), 1.79-1.62 (m 2H), 1.32-1.13 (m, 9H), 0.93-0.88 (m, 2CH₃); ¹³C NMR (CD₃OD) d 166.1, 160.3 (d, J=242.3 Hz), 148.1 (d, J=11.9Hz), 126.4 (d, J=2.9 Hz), 117.8 (d, J=9.4 Hz), 109.9 (d, J=22.9 Hz),105.7 (d, J=26.1 Hz), 68.6, 65.1, 56.3, 55.4, 46.6, 37.5, 37.0, 33.6,33.4, 30.1, 29.9, 24.0, 17.2, 14.4.

The product was dissolved in MeOH/Et₂O and oxalic acid dissolved in Et₂Owas added. The formed crystals were filtered and washed with acetone togive the title compound as oxalic salt (0.176 g). HPLC-MS (ammoniumacetate) [M+H]⁺=363.29.

(R)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(111MF28)

The compound(S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20) (0.501 g, 1.43 mmol) and 4-propyloxypiperidine (0.205 g, 1.43mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF28) (0.375 g, 71%). ¹H NMR (CDCl₃) d 7.12-7.08(m, 1H), 6.74-6.69 (m, 2H), 4.59 (q, J=15.0 Hz, J=31.0 Hz, 2H),4.01-3.88 (m, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.77 (t,J=6.3 Hz, 1H), 2.63 (t, J=5.6 Hz, 1H), 2-26-2.12 (m, 3H), 2.04-1.96 (m,2H), 1.88-1.84 (m, 2H), 1.62-1.50 (m, 4H), 0.93-0.87 (m, 6H); ¹³C NMR(CDCl₃) d 164.2, 158.9 (d, J=241.9 Hz), 146.5 (d, J=12.1 Hz), 125.2 (d,J=3.0 Hz), 116.1 (d, J=9.6 Hz), 109.0 (d, J=22.3 Hz), 105.2 (d, J=25.8Hz), 75.2, 69.8, 67.8, 63.5, 52.8, 51.8, 45.5, 31.9, 31.8, 29.4, 23.5,17.0, 10.8.

To the pure compound (0.375 g, 1.03 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.097 g, 1.08 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.41 g, 88%); HPLC-MS (ammonium acetate)[M+H]⁺=365.3.

(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(111MF29)

The compound(S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20)(0.515 g, 1.47 mmol) and 4-butylidenepiperidine (0.205 g, 1.47mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF29) (0.393 g, 73%). ¹H NMR (CDCl₃) d 7.17-7.12(m, 1H), 6.74-6.69 (m, 2H), 5.15-5.11 (t, J=7.2 Hz, 1H), 4.61 (q, J=15.2Hz, 2H), 4.04-3.92 (m, 2H), 2.48-2.40 (m, 2H), 2.32-2.13 (m, 9H), 1.96(q, J=7.2 Hz, 2H), 1.38-1.30 (m, 2H), 0.91-0.86 (m, 6H); ¹³C NMR (CDCl₃)d 164.1, 158.9 (d, J=243.4 Hz), 146.5 (d, J=11.9 Hz), 136.1, 125.2 (d,J=3.0 Hz), 128.9, 116.2 (d, J=22.7 Hz), 109.0 (d, J=22.7 Hz), 105.2 (d,J=26.2 Hz), 67.8, 63.7, 56.5, 55.7, 54.6, 36.3, 29.3, 28.5, 23.3, 17.1,13.9.

To the pure compound (0.393 g, 1.09 mmol) dissolved in diethyl ether (4mL) was added oxalic acid (0.103 g, 1.14 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.46 g, 94%); HPLC-MS (ammonium acetate)[M+H]⁺=361.3.

(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK05)

A microwave vial was charged with(S)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20) (0.047 g, 0.13 mmol) and 3-butyl-8-azabicyclo[3,2,1]octane(0.039 g, 0.23 mmol) in MeCN (2 mL) and sealed. After microwaveirradiation, 100° C., 60 min, the reaction mixture was purified bycation exchange CC followed by flash CC (SiO₂; CH₂Cl₂/MeOH 50:1) to givethe title compound (112KK05) (0.017 g, 33%). ¹H NMR (CD₃OD) d 7.34-7.30(m, 1H), 6.80-6.75 (m, 2H), 4.61 (ABq, J=18.8 Hz, J=15.1 Hz, CH₂), 4.04(dd, J=14.3 Hz, J=5.9 Hz, 1H), 3.93 (dd, J=14.3 Hz, J=8.2 Hz, 1H),3.18-3.10 (m, 2H), 2.36-2.23 (m, 2H), 2.03-1.85 (m, 3H), 1.62-1.45 (m,5H), 1.36-1.14 (m, 8H), 0.92-0.87 (m, 2 CH₂); ¹³C NMR (CD₃OD) d 166.2,160.4 (d, J=242.3 Hz), 148.1 (d, J=11.9 Hz), 126.3 (d, J=2.9 Hz), 118.1(d, J=9.7 Hz), 109.8 (d, J=22.9 Hz), 105.7 (d, J=26.5 Hz), 68.6, 62.5,61.2, 58.3, 46.4, 39.0, 37.9, 32.1, 30.2, 29.0, 27.8, 27.2, 23.9, 17.2,14.4.

The product was dissolved in MeOH/Et₂O and oxalic acid dissolved in Et₂Owas added. The formed crystals were filtered and washed with acetone togive the title compound as oxalic salt (0.016 g). HPLC-MS (ammoniumacetate) [M+H]⁺=389.34.

(R)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(111MF30)

The compound(S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(111MF20) (0.208 g, 0.59 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane(0.106 g, 0.58 mmol) were mixed according to GP16. CC (SiO₂;Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF30)(0.070 g, 29%). ¹H NMR (CDCl₃) d 7.23-7.19 (m, 1H), 6.66-6.60 (m, 2H),4.60-4.46 (m, 2H), 4.05-3.99 (m, 1H), 3.95-3.90 (m, 1H), 3.06-3.03 (m,1H), 2.99-2.96 (m, 1H), 2.24-2.19 (m, 1H), 2.07-1.94 (m, 3H), 1.90-1.73(m, 3H), 1.60-1.45 (m, 3H), 1.33-1.25 (m, 2H), 1.24-1.12 (m, 8H),0.83-0.78 (m, 6H); ¹³C NMR (CDCl₃) d 164.1, 158.8 (d, J=243.3 Hz), 146.4(d, J=11.5 Hz), 125.1 (d, J=3.1 Hz), 116.6 (d, J=9.3 Hz), 108.9 (d,J=22.8 Hz), 105.0 (d, J=25.7 Hz), 67.7, 60.9, 58.8, 58.1, 45.4, 38.3,36.8, 36.6, 32.1, 31.6, 28.5, 28.4, 28.1, 27.0, 22.8, 17.0, 14.2.

To the pure compound (0.070 g, 0.17 mmol) dissolved in diethyl ether (1mL) was added oxalic acid (0.016 g, 0.18 mmol) in diethyl ether (1 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.082 g, 96 %); HPLC-MS (ammoniumacetate) [M+H]⁺=402.56

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methyl-propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF38)

The compound(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol)were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) and prepHPLC gave the title compound (111MF38) (0.245 g, 27%). ¹H NMR (CDCl₃) d6.89 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, J=8.8Hz, 1H), 4.54 (q, J=32.4, J=14.8, 2H), 3.94-3.90 (m, 2H), 3.77 (s, 3H),2.90 (d, J=11.2 Hz, 1H), 2.72 (d, J=10.8 Hz, 1H), 2.25-2.10 (m, 3H),1.93 (t, J=11.2 Hz, 1H), 1.80 (t, J=11.2 Hz, 1H), 1.61 (d, J=10.8 Hz,2H), 1.31-1.19 (m, 9H), 0.90-0.86 (m, 6H); ¹³C NMR (CDCl₃) d 165.3,155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5,45.5, 36.5, 36.0, 32.9, 32.5, 29.2, 29.2, 23.1, 16.9, 14.3.

To the pure compound (0.245 g, 0.65 mmol) dissolved in diethyl ether (2mL) was added oxalic acid (0.062 g, 0.68 mmol) in diethyl ether (2 mL).The formed crystals filtered and washed with diethyl ether to give thetitle compound as oxalic salt (0.229 g, 75%) HPLC-MS (ammonium acetate)[M+H]⁺=375.3.

(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF39)

The compound(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36) (0.612 g, 1.69 mmol) and 4-butylidenepiperidine (0.212 g, 1.5mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF39) (0.489 g, 77%). ¹H NMR (CDCl₃) d 6.90 (d,J=8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.50 (dd, J=8.4 Hz, J=2.8 Hz,1H), 5.11 (t, J=7.6 Hz, 1H), 4.54 (q, J=14.4 Hz, 2H), 3.97-3.94 (d,J=6.8 Hz, 2H), 3.78 (s, 3H), 2.48-2.41 (m, 2H), 2.33-2.23 (m, 5H),2.20-2.13 (m, 4H), 1.96 (q, J=7.4 Hz, 2H), 1.40-1.29 (m, 2H), 0.91-0.86(m, 6H); ¹³C NMR (CDCl₃) d 165.3, 155.5, 139.8, 136.5, 129.8, 122.5,117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3,29.2, 28.4, 23.3, 16.9, 13.9; HPLC-MS; (ammonium acetate) [M+H]⁺=373.3.

(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF40)

The compound(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36) (0.239 g, 0.66 mmol) and 3-Butyl-8-aza-bicyclo[3.2.1]octane(0.100 g, 0.60 mmol) were mixed according to GP16. CC (SiO₂;Heptane/EtOAc 4:1-4) gave the title compound (111MF40) (0.163 g, 61%).¹H NMR (CDCl₃) d 6.88 (d, J=8.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.49(dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.61-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.77(s, 3H), 3.17-3.04 (m, 2.35-2.29 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.13(m, 6H), 0.88 (m, 3H); ¹³C NMR (CDCl₃) d 165.4, 155.6, 139.8, 129.8,117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4,36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammoniumacetate) [M+H]⁺=401.3.

(R)-6-Methoxy-4-[2-methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one(111MF41)

The compound(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane(0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiO₂;heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41)(0.101 g, 39%). ¹H NMR (CDCl₃) d 6.89 (d, J=8.8 Hz, 1H), 6.81 (d, J=2.8Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d,J=6.8 Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H),2.20-1.79 (m; 7H), 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m,6H); ¹³C NMR (CDCl₃) d 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8,68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4,28.4, 28.0, 27.3, 22.8, 16.8, 14.2; HPLC-MS (ammonium acetate)[M+H]⁺=415.3.

(R)-6-Methoxy-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(111MF42)

The compound(S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(111MF36) (0.556 g, 1.5 mmol) and 4-propyloxypiperidine (0.20 g, 1.4mmol) were mixed according to GP16. CC (SiO₂; Heptane/EtOAc 4:1-4) gavethe title compound (111MF42) (0.30 g, 53%). ¹H NMR (CDCl₃) d 6.89 (d,J=8.8 Hz, 1H), 6.85 (d, 2.8 Hz, 1H), 6.49 (dd, J=8.8 Hz, J=2.8 Hz, 1H),4.53 (q, J=14.6 Hz, 2H), 3.93 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.38 (t,J=6.8 Hz, 2H), 3.29-3.22 (m, 1H), 2.80-2.77 (t, 6.4 Hz, 1H), 2.65-2.61(t, J=6.0 Hz, 1H), 2.29-2.00 (m, 5H), 1.88-1.84 (m, 2H), 1.65-1.53 (m,4H), 0.94-0.87 (m, 6H); ¹³C NMR (CDCl₃) d 165.4, 155.5, 139.8, 129.8,117.2, 107.1, 103.3, 75.1, 69.7, 68.0, 63.7, 56.0, 52.5, 51.9, 45.4,31.6, 31.5, 29.2, 23.5, 16.9, 10.8; HPLC-MS (ammonium acetate)[M+H]⁺=377.3.

General Procedure 17 (GP17)

A 7 mL vial was charged with the crude4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (1 equiv),Et₃N (0.5 mL) and the secondary amine (1.2-1.5 equiv). This mixture wasshaken at 60° C. for 72 h and thereafter diluted with MeOH (10 mL) andconcentrated with basic Al₂O₃ (2 g) and purified by flashchromatography.

(R)-6-Methyl-4-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(101IS69)

Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(0.23 g), 4-propyloxypiperidine (0.12 g, 0.81 mmol) and Et₃N (0.5 mL)were reacted according to GP17. Flash CC (SiO₂; CH₂Cl₂/acetone/MeOH90:5:5) gave the title compound (0.20 g, 83%). ¹H NMR (CD₃OD) δ 6.97(brs, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.75 (dm, J=8.0 Hz, 1H), 4.47 (brs,2H), 3.97 (dd, J=6.4, 14.4 Hz, 1H), 8.82 (dd, J=7.2, 14.4 Hz, 1H), 3.44(brs, 1H), 3.33 (t, J=6.8 Hz, 2H), 3.10-2.90 (m, 2H), 2.90-2.6 (m, 3H),2.29 (m, 1H), 2.24 (s, 3H), 1.98-1.86 (m, 2H), 1.78-1.64 (m, 2H), 1.47(tq, J=14.4, 7.2 Hz, 2H), 0.92 (d, J=6.4 Hz), 0.83 (t, J=7.2 Hz); ¹³CNMR (CD₃OD) δ 166.4, 143.8, 132.8, 128.3, 124.7, 116.7, 116.1, 69.9,67.4, 61.5, 50.7, 50.5, 44.1, 28.9, 28.6, 23.0, 20.0 15.6, 9.8.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.204g). HPLC-MS (ammonium acetate) [M+H]⁺=361.3.

(R)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS71-A)

Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(0.34 g), Et₃N (0.5 mL) and 4-butylidenepiperidine (0.17 g, 1.2 mmol)were reacted according to GP17. Flash CC (SiO₂; CH₂Cl₂/acetone/MeOH90:7:3) gave the title compound (0.22 g, 58%). ¹H NMR (CD₃OD) δ 7.01 (s,1H), 6.86 (d, J=8.0 Hz, 1H), 6.82 (dm, J=8.0 Hz, 1H), 5.12 (t, J=7.2 Hz,1H), 4.52 (ABq, J=14.8, 20.8 Hz, 2H), 4.03 (dd, J=5.6, 14.4 Hz, 1H),3.91 (dd, J=8.0, 14.4 Hz, 1H), 2.48-2.34 (m, 2H), 2.33-2.11 (m, 8H),2.31 (s, 3H), 1.96 (q, J=7.2 Hz, 2H), 1.34 (m, 2H), 0.91-0.86 (m, 6H);¹³C NMR (CD₃OD) δ165.9, 143.9, 136.0, 132.4, 128.3, 124.3, 122.4, 116.6,116.2, 67.4, 63.6, 56.3, 55.4, 45.0, 28.92, 28.85, 28.0, 23.0, 20.0,15.9, 12.8.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.236g). HPLC-MS (ammonium acetate) [M+H]⁺=367.3.

(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS71-D)

Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(0.30 g), Et₃N (0.5 mL) and 4-butylpiperidine (0.15 g, 1.0 mmol) werereacted according to GP17. Flash CC (SiO₂; CH₂Cl₂/acetone/MeOH 90:7:3)gave the title compound (0.26 g, 84%). ¹H NMR (CD₃OD) δ 7.00 (s, 1H),6.86 (d, J=8.0 Hz, 1H), 6.81 (dm, J=8.0 Hz, 1H), 4.52 (ABq, J=14.4, 20.8Hz, 2H), 3.99 (dd, J=6.0, 14.4 Hz, 1H), 3.90 (dd, J=8.4, 14.4 Hz, 1H),2.97 (brd, J=11.2 Hz, 1H), 2.82 (brd, J=8.4 Hz, 1H), 2.39-2.10 (m, 2H),2.31 (s, 3H), 2.07-1.88 (m, 2H), 1.73-1.62 (m, 2H), 1.35-1.18 (m, 9H),0.94-0.08 (m, 6H); ¹³C NMR (CD₃OD) δ 166.0, 143.8, 132.4, 128.3, 124.3,116.6, 116.2, 67.4, 63.6, 55.0, 54.2, 44.8, 36.2, 35.6, 32.1 (br), 28.9,28.8, 22.8, 20.0, 15.9, 13.2.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.253g). HPLC-MS (ammonium acetate) [M+H]⁺=359.3.

(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS71-B3)

Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(0.19 g, 0.54 mmol), Et₃N (0.5 mL) and 3-butyl-8-azabicyclo[3.2.1]octane(0.10 g, 0.61 mmol) were reacted according to GP17. Flash CC (SiO₂;CH₂Cl₂/i-PrOH 92:8) gave the title compound (0.13 g, 62%). ¹H NMR(CD₃OD) δ 7.05 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.81 (dm, J=8.4 Hz, 1H),4.52 (ABq J=14.8, 24.8 Hz, 2H), 4.05 (dd, J=5.6, 14.0 Hz, 1H), 3.94 (dd,J=8.8, 14.0 Hz, 1H), 3.05-3.16 (m, 2H), 2.35-2.14 (m, 2H), 2.31 (s, 3H),2.05-1.78 (m, 3H), 1.63-1.40 (m, 5H), 1.36-1.12 (m, 5H), 0.99 (d, J=6.4Hz, 3H), 0.90 (t, J=6.8 Hz, 3H); ¹³C NMR (CD₃OD) δ 167.4, 144.9, 133.7,129.2, 125.6, 117.7, 117.3, 68.5, 63.2 (br), 62.5 (br), 56.0 (Br), 43.3,37.8 (br), 31.3, 30.5, 30.0, 28.3, 26.7, 26.4, 23.7, 21.0, 16.8, 14.2.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.104g). HPLC-MS (ammonium acetate) [M+H]⁺=349.3.

(R)-4-[3-(3-Pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(101IS71-C3)

Crude (S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(0.15 g), Et₃N (0.5 mL) and 3-pentyl-8-azabicyclo[3.2.1]octane (95 mg,5.2 mmol) were reacted according to GP17. Flash CC (SiO₂; CH₂Cl₂/I—PrOH92:8) gave the title compound (0.12 g, 68%). ¹H NMR (CD₃OD) δ 7.06 (s,1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (brd, J=8.0 Hz, 1H), 4.52 (ABq,J=14.8, 27.2 Hz, 2H), 4.06 (dd, J=5.6, 14.2 Hz, 1H), 4.96 (dd, J=8.8,14.2 Hz, 1H), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.31 (s, 3H),2.04-181 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m,6H); ¹³C NMR (CD₃OD) δ167.2, 145.1, 133.6, 129.4, 125.5 117.7, 117.5,68.7, 61.6, 60.2, 58.6, 46.1, 49.6, 36.9, 33.1, 32.4, 29.6, 29.5, 28.5,27.8, 23.7, 21.18, 17.0, 14.4.

The product was dissolved in diethyl ether and oxalic acid (1.1 equiv)dissolved in diethyl ether was added. The formed crystals were filteredand washed with acetone to give the title compound as oxalic salt (0.128g). HPLC-MS (ammonium acetate) [M+H]⁺=399.3.

1-[3-(4-Propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(85LM32)

A 4 mL vial was charged with crude1-(3-chloro-propyl)-3,4-dihydro-1H-quinolin-2-one (85LM31) (0.200 g),4-propoxy-piperidine (79KS-66) (0.130 g, 0.897 mmol), potassiumcarbonate (0.247 g, 1.79 mmol) and sodium iodide (0.269 g, 1.79 mmol) inMeCN (2 mL) and shaken at 50° C. for 20 h. The reaction mixture wasquenched with water (1 mL), and the product was extracted into EtOAc(3×1 mL). The combined organic layers were dried over Na₂SO₄, evaporatedand purified by flash CC (SiO₂; MeOH/DCM 0:1→3:7) to give the titlecompound (85LM32) (0.012 g, total yield 3%). ¹H NMR (CDCl₃) δ 7.25 (t,J=7.4 Hz, 1H), 7.18-7.08 (m, 2H), 6.98 (t, J=7.4 Hz, 1H), 3.98 (t, J=7.6Hz, CH₂), 3.38 (t, J=6.8 Hz, CH₂), 3.35-3.25 (m, 1H), 2.87 (t, J=7.6 Hz,CH₂), 2.80-2.70 (m, 2H), 2.65-2.60 (m, 2H), 2.45-2.35 (m, 2H), 2.20-2.10(m, 2H), 1.95-1.80 (m, 4H), 1.65-1.50 (m, 4H), 0.95 (t, J=7.6 Hz, CH₃);¹³C NMR (CDCl₃) δ 170.2, 140.0, 128.2, 127.5, 126.6, 122.8, 115.3, 70.0,56.0, 51.8, 40.5, 32.0, 31.5, 25.8, 25.2, 22.8, 10.7; HPLC-MS (ammoniumacetate) [M+H]⁺=331.3.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one(92LH81)

A 4 mL vial was charged with1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79)(0.090 g, 0.37 mmol), 4-butylpiperidine (0.078 g, 0.55 mmol), KI (0.091g, 0.55 mmol), and K₂CO₃ (0.076 g, 0.55 mmol) in MeCN and shaken at 50°for 20 h. The reaction mixture was quenched with water, and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flash CC(SiO₂; EtOAc) to give the title compound (92LH81) (0.090 g, 70%). ¹H NMR(CD₃OD) d 7.19-7.15 (m, 1H), 6.99-6.97 (m, 2H), 3.97 (t, J=6.4 Hz, CH₂),2.90-2.87 (m, 4H), 2.59 (t, J=7.6 Hz, CH₂), 2.38 (t, J=7.6 Hz, CH₂);1.96-1.78 (m, 4H), 1.67 (d, J=9.6 Hz, 2H), 1.29-1.22 (m, 9H), 0.90-0.88(m, 3H); ¹³C NMR (CD₃OD) d 172.1, 160.0 (d, J=241.8 Hz), 136.7 (d, J=2.3Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.1 Hz), 115.9 (d, J=23.1 Hz),114.6 (d, J=22.7 Hz), 57.0, 55.0, 41.6, 37.4, 36.9, 33.1, 32.4, 30.1,26.2, 25.5, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H⁺]=347.33.

6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH70)

A 4 mL vial was charged with1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (92LH79)(0.242 g, 1.00 mmol), 4-propoxypiperidine (0.143 g, 1.00 mmol), KI(0.250 g, 1.50 mmol), and K₂CO₃ (0.207 g, 1.50 mmol) in MeCN (2 mL) andshaken at 40° for 20 h. The reaction mixture was quenched with water,and the product extracted into EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash CC (SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the title compound(107LH70) (0.165 g, 47%). ¹H NMR (CD₃OD) d 7.19-7.15 (m, 1H), 7.01-6.97(m, 2H), 3.96 (t, J=7.4 Hz, CH₂), 3.40 (t, J=6.6 Hz, CH₂), 3.35-3.30 (m,3H), 2.88 (t, J=6.8 Hz, 2H), 2.76 (m, 2H), 2.60-2.57 (m, 2H), 2.43-2.39(m, 2H), 2.22-2.17 (m, 2H), 1.90-1.78 (m, 4H), 1.61-1.50 (m, 4H), 0.91(t, J=7.4 Hz, CH₃); ¹³C NMR (CD₃OD) d 172.2, 160.0 (d, J=242.2 Hz),136.7 (d, J=2.3 Hz), 130.6 (d, J=7.7 Hz), 117.8 (d, J=8.5 Hz), 115.9 (d,J=23.1 Hz), 114.64 (d, J=22.3 Hz), 75.6, 70.7, 56.5, 52.0, 41.6, 32.4,31.8, 26.1, 25.5, 24.2, 11.0; HPLC-MS (ammonium acetate) [M+H⁺]=349.30.

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-3,4-dihydro-1H-quinolin-2-one(107LH71-1)

A 4 mL vial was charged with crude(R,S)-1-(3-chloro-2-methylpropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one(107LH68) (0.154 g), 4-butylpiperidine (0.141 g, 1.0 mmol), KI (0.250 g,1.5 mmol), and K₂CO₃ (0.207 g, 1.5 mmol) in DMF (2 mL) and shaken at100° for 20 h. The reaction mixture was quenched with water, and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The crude product was purifiedby cation exchange CC and flash CC (SiO₂; EtOAc) to give the titlecompound (107LH77-1) (0.069 g, total yield 13%). ¹H NMR (CD₃OD) d7.22-7.18 (m, 1H), 7.00-6.93 (m, 1H), 3.94 (d, J=6.8 Hz, 2H), 2.91-2.86(m, 3H), 2.74 (d, J=10.2 Hz, 1H), 2.62-2.58 (m, 2H), 2.24-2.02 (m, 3),1.90-1.81 (m, 2H), 1.66-1.61 (m, 2H), 1.30-1.19 (m, 9H), 0.89 (t, J=6.6Hz, CH₃), 0.86 (d, J=6.7 Hz, CH₃); ¹³C NMR (CD₃OD) d 172.7, 160.0 (d,J=241.8Hz), 136.7 (d, J=2.7 Hz), 130.9 (d, J=8.1 Hz), 118.4 (d, J=8.1Hz), 115.9 (d, J=23.5 Hz), 114.4 (d, J=22.7 Hz), 65.0, 56.1, 55.6, 46.9,37.5, 37.0, 33.5, 33.4, 32.6, 30.1, 30.1, 26.2, 24.0, 17.2, 14.4.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.076 g). HPLC-MS(ammonium acetate) [M+H]⁺=361.32.

(R,S)-6-Fluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH71-2)

A 4 mL vial was charged with crude(R,S)-1-(3-chloro-2-methylpropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one(107LH68) (0.154 g), 4-propoxypiperidine (0.143 g, 1.0 mmol), KI (0.250g, 1.5 mmol), and K₂CO₃ (0.207 g, 1.5 mmol) in DMF (2 mL) and shaken at100° for 20 h. The reaction mixture was quenched with water, and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The crude product was purifiedby cation exchange CC and flash CC (SiO₂; EtOAc) to give the titlecompound (107LH77-2) (0.053 g, total yield 10%). ¹H NMR (CD₃OD) d7.23-7.19 (m, 1H), 7.00-6.95 (m, 1H), 3.95 (d, J=7.0 Hz, 2H), 3.41 (t,J=6.6 Hz, CH₂), 3.31-3.27 (m, 1H), 2.90 (t, J=6.6 Hz, 2H), 2.74-2.71 (m,1H), 2.64-2.58 (m, 3H), 2.26-2.00 (m, 5H), 1.89-1.85 (m, 2H), 1.60-1.49(m, 4H), 0.91 (t, J=7.4 Hz, CH₃), 0.86 (d, J=6.7 Hz, CH₃); 1³C NMR(CD₃OD) d 172.7, 160.0 (d, J=242.2 Hz), 136.7 (d, J=2.7 Hz), 130.9 (d,J=7.7 Hz), 118.3 (d, J=8.1 Hz), 115.9 (d, J=23.1 Hz), 114.5 (d, J=22.7Hz), 76.4, 70.7, 64.4, 53.2, 52.8, 46.9, 32.5, 32.4, 32.3, 30.3, 26.17,26.15, 24.2, 17.1, 11.0.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.048 g). HPLC-MS(ammonium acetate) [M+H]⁺=363.30.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-3,4-dihydro-1H-quinolin-2-one(107LH36)

A reaction flask was charged with 6-chloro-3,4-dihydro-1H-quinolin-2-one(107LH30) (0.100 g, 0.55 mmol) in dry DMF (2 mL) under Argon. NaH (60%in oil, 0.024 g, 0.60 mmol) was added and the mixture was stirred at rtfor 0.5 h. Then 1-bromo-3-chloropropane (0.087 g, 0.55 mmol) was addedfollowed by stirring at 30° for 20 h. The reaction mixture was quenchedwith water, and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudematerial was dissolved in MeCN (3 mL) followed by addition of4-butylpiperidine (0.078 g, 0.055 mmol), KI (0.166 g, 1.00 mmol), andK₂CO₃ (0.138 g, 1.00 mmol) and shaken at 50° for 2 days. The reactionmixture was quenched with water, and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by prep RP-HPLC to give the titlecompound (107LH36) (0.047 g, 24%). ¹H NMR (CD₃OD) d 7.25-7.13 (m, 3H),3.96 (t, J=7.2 Hz, CH₂), 2.95-2.86 (m, 4H), 2.61-2.57 (m, 2H), 2.45-2.41(m, 2H), 2.04-1.98 (m, 2H), 1.87-1.79 (m, 2H), 1.28-1.18 (m, 9H), 0.90(t, J=7.0 Hz, CH₃); ¹³C NMR (CD₃OD) d 172.3, 139.2, 130.2, 129.3, 128.9,128.4, 117.8, 56.8, 54.9, 41.4, 37.2, 36.6, 32.9, 32.4, 30.0, 26.0,25.3, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H⁺]=363.28.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-3,4-dihydro-1H-quinolin-2-one(107LH18-1)

A 4 mL vial was charged with crude1-(3-chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14)(0.128 g), 4-butylpiperidine (0.076 g, 0.54 mmol), KI (0.166 g, 1.00mmol), and K₂CO₃ (0.138 g, 1.00 mmol) in MeCN (2 mL) and shaken at 50°for 20 h. The reaction mixture was quenched with water, and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flash CC(SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-1)(0.088 g, total yield 41%). ¹H NMR (CD₃OD) d 7.07-7.01 (m, 3H), 3.94 (t,J=7.4 Hz, CH₂), 2.90-2.80 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.33 (m, 2H),2.27 (s, 3H, CH₃), 1.95-1.90 (m, 2H), 1.85-1.79 (m, 2H), 1.66 (d, J=9.8Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8 Hz, CH₃); ¹³C NMR (CD₃OD) d172.4, 137.9, 134.1, 129.8, 129.0, 128.0, 116.3, 57.1, 55.0, 41.3, 37.4,36.8, 33.1, 32.8, 30.1, 26.2, 25.5, 23.9, 20.7, 14.4; HPLC-MS (ammoniumacetate) [M+H⁺]=343.33.

6-Methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH 18-2)

A 4 mL vial was charged with1-(3-Chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14)(0.128 g), 4-propoxypiperidine (0.079 g, 0.54 mmol), KI (0.166 g, 1.0mmol), and K₂CO₃ (0.138 g, 1.0 mmol) in MeCN (2 mL) and shaken at 50°for 20 h. The reaction mixture was quenched with water, and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flash CC(SiO₂; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-2)(0.108 g, total yield 50%). ¹H NMR (CD₃OD) d 7.05-7.00 (m, 3H), 3.95 (t,J=7.2, CH₂), 3.41-3.30 (m, 3H), 2.84-2.76 (m, 4H), 2.57-2.53 (m, 2H),2.27-2.43 (m, 2H), 2.27 (s, 3H, CH₃), 2.27-2.22 (m, 2H), 1.90-1.81 (m,4H), 1.63-1.52 (m, 4H), 0.91 (t, J=7.4 Hz, CH₃); ¹³C NMR (CD₃OD) d172.4, 137.8, 134.0, 129.8, 129.0, 128.0, 116.2, 75.3, 70.7, 56.5, 51.9,41.2, 32.8, 31.7, 26.2, 25.5, 24.3, 20.7, 11.0; HPLC-MS (ammoniumacetate) [M+H⁺]=345.30.

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-3,4-dihydro-1H-quinolin-2-one(107LH21)

A reaction flask was charged with 7-fluoro-3,4-dihydro-1H-quinolin-2-one(97LH36) (0.080 g, 0.48 mmol) in dry DMF (2 mL) under Argon. NaH (60% inoil, 0.021 g, 0.53 mmol) was added and the mixture was stirred at rt for0.5 h. Then 1-bromo-3-chloropropane (0.075 g, 0.48 mmol) was addedfollowed by stirring at rt for 20 h. The reaction mixture was quenchedwith water, and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudematerial was dissolved in MeCN (3 mL) followed by addition of4-butylpiperidine (0.071 g, 0.50 mmol), KI (0.166 g, 1.00 mmol), andK₂CO₃ (0.138 g, 1.00 mmol) and shaken at 50° for 4 days. The reactionmixture was quenched with water, and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash CC (SiO₂; EtOAc) to givethe title compound (107LH21) (0.062 g, 37%). ¹H NMR (CD₃OD) d 7.20-7.17(m, 1H), 7.01-6.98 (m, 1H), 6.76-6.72 (m, 1H), 3.95 (t, J=7.4 Hz, CH₂),2.93-2.84 (m, 4H), 2.61-2.57 (m, 2H), 2.42-2.38 (m, 2H), 2.00-1.94 (m,2H), 1.84-1.80 (m, 2H), 1.68 (d, J=10.0 Hz, 2H), 1.30-1.22 (m, 9H), 0.89(t, J=6.8 Hz, CH₃); HPLC-MS (ammonium acetate) [M+H⁺]=347.31.

1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-3,4-dihydro-1H-quinolin-2-one(107LH28)

A 4 mL vial was charged with1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11,3)(0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083g, 0.50 mmol), and K₂CO₃ (0.069 g, 0.50 mmol) in MeCN and shaken at 50°.The reaction mixture was quenched with water, and the product extractedinto EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash CC (SiO₂;EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g,74%). ¹H NMR (CD₃OD) d 7.15 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H),6.92 (d, J=7.4 Hz), 4.00 (t, J=7.2 Hz, CH₂), 3.10 (d, J=12.1 Hz, 2H),2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m,2H), 2.29 (s, CH₃), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7 Hz, 2H),1.31-1.24 (m, 9H), 0.90 (t, J=6.8 Hz, CH₃); ¹³C NMR (CD₃OD) d 172.7,140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0,32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammoniumacetate) [M+H⁺]=343.36.

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-3,4-dihydro-1H-quinolin-2-one(107LH29)

A 4 mL vial was charged with1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-13,1)(0.117 g, 0.49 mmol), 4-butylpiperidine (0.071 g, 0.50 mmol), KI (0.166g, 1.00 mmol), and K₂CO₃ (0.138 g, 1.00 mmol) in MeCN and shaken at 50°.The reaction mixture was quenched with water, and the product extractedinto EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash CC (SiO₂;EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g,74%). ¹H NMR d 7.06 (d, J=7.4 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J=7.6 Hz,1H), 3.97 (t, J=7.4 Hz, CH₂), 2.91 (d, J=11.2 Hz, 2H), 2.82 (t, J=6.8Hz, CH₂), 2.57-2.54 (m, 2H), 2.41-2.37 (m, 2H), 2.33 (s, CH₃), 1.98-1.92(m, 2H), 1.87-179 (m, 2H), 1.68 (d, J=9.6 Hz, 2H), 1.30-1.17 (m, 9H),0.89 (t, J=6.8 Hz, CH₃); ¹³C NMR (CO₃OD) d 172.7, 140.1, 138.5, 128.9,125.1, 124.9, 117.0, 57.0, 55.0, 41.3, 37.3, 36.8, 33.1, 30.1, 25.8,25.6, 23.9, 21.6, 14.4; HPLC-MS (ammonium acetate) [M+H]⁺=343.37.

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one(112KK06)

A 4 mL vial was charged with1-(3-chloropropyl)-7-fluoro-6-methyl-3,4-dihydro-1H-quinolin-2-one(112KK01) (0.047 g, 0.18 mmol), 4-butylpiperidine (0.039 g, 0.28 mmol),NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in MeCN (2 mL)and shaken at 50° for 20 h. The reaction mixture was quenched withwater, and the product extracted into EtOAc. The combined organic layerswere purified by cation exchange CC followed by purification by flash CC(SiO₂; MeOH/DCM 1:10) to give the title compound (112KK06) (0.022 g,34%). ¹H NMR (CD₃OD) d 7.05 (d, J=8.4 Hz, 1H), 6.93 (d, J=11.7 Hz, 1H),3.93 (t, J=7.2 Hz, CH₂), 2.93 (d, J=11.1 Hz, 2H), 2.83 (t, J=6.9 Hz,CH₂), 2.60-2.56 (m, 2H), 2.44-2.40 (m, 2H), 2.19 (D, J=1.8 Hz, CH₃)2.03-1.98 (m, 2H), 1.86-1.79 (m, 2H), 1.69 (d, J=11.0 Hz, 2H), 1.31-1.19(m, 9H), 0.89 (t, J=6.6 Hz, CH₃); ¹³C NMR (CD₃OD) d 172.4, 161.7 (d,J=241.0 Hz), 139.5 (d, J=10.0 Hz), 131.7 (d, J=6.1 Hz), 123.5 (d, J=3.6Hz), 119.9 (d, J=17.4 Hz), 104.0 (d, J=28.1 Hz), 56.8, 55.0, 41.5, 37.3,36.7, 33.0, 32.8, 30.1, 25.5, 25.3, 23.9, 14.4, 13.7.

The product was dissolved in MeOH/Et₂O and oxalic acid dissolved in Et₂Owas added. The formed crystals were filtered and washed with acetone togive the title compound as oxalic salt (0.018 g). HPLC-MS (ammoniumacetate) [M+H]⁺=361.35.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(112KK07)

A 4 mL vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (112KK03)(0.123 g, 0.47 mmol), 4-butylpiperidine (0.074 g, 0.52 mmol), NaI (0.100g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in MeCN (2 mL) and shakenat 50° for 20 h. The reaction mixture was quenched with water, and theproduct extracted into EtOAc. The combined organic layers were purifiedby cation exchange CC followed by purification by flash CC (SiO₂;MeOH/DCM 1:10) to give the title compound (112KK07) (0.097 g, 57%). ¹HNMR (CD₃OD) d 7.20-7.09 (m, 2H), 3.91 (t, J=7.2 Hz, CH₂), 2.90-2.82 (m,4H), 2.59-2.55 (m, 2H), 2.38-2.34 (m, 2H), 1.97-1.91 (m, 2H), 1.82-1.75(m, 2H), 1.66 (d, J=9.8 Hz, 2H), 1.28-1.16 (m, 9H), 0.87 (t, J=6.7 Hz,CH₃; ¹³C NMR (CD₃OD) d 172.1, 150.4 (q, J=243.2 Hz, J=13.2 Hz), 146.9(q, J=243.2 Hz, J=12.6 Hz), 137.3 (q, J=8.1 Hz, J=2.9 Hz), 124.9 (q,J=5.8 Hz, J=3.9 Hz), 117.6 (d, J=18.7 Hz), 106.4 (d, J=22.6 Hz), 56.8,55.0, 41.8, 37.4, 36.8, 33.1, 32.4, 30.1, 25.5, 25.3, 23.9, 14.4.

The product was dissolved in MeOH/Et₂O and oxalic acid dissolved in Et₂Owas added. The formed crystals were filtered and washed with acetone togive the title compound as oxalic salt (0.046 g). HPLC-MS (ammoniumacetate) [M+H]⁺=365.32.

6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(122LH7)

A 4 mL vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (112KK03)(0.286 g, 1.1 mmol), 4-propoxypiperidine (0.160 g, 1.1 mmol), KI (0.250g, 1.5 mmol), and K₂CO₃ (0.207 g, 1.54 mmol) in MeCN (2.5 mL) and shakenat 40° for 2 days. The reaction mixture was quenched with water, and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The crude product was purifiedby cation exchange CC followed by flash CC (SiO₂; EtOAc) and then prepRP-HPLC to give the title compound (122LH07) (0.165 g, 41%). ¹H NMR(CD₃OD) d 7.22-7.11 (m, 2H), 3.94 (t, J=7.2 Hz, CH₂), 3.42-3.35 (m, 3H),2.89-2.83 (m, 4H), 2.62-2.51 (m, 4H), 2.40-2.36 (m, 2H), 1.95-1.82 (m,4H), 1.69-1.51 (m, 4H), 0.91 (t, J=7.2 Hz, CH₃); ¹³C NMR (CD₃OD) d172.0, 150.3 (q, J=243.3 Hz, J=13.5 Hz), 146.9 (q, J=243.3 Hz, J=12.7Hz), 137.3 (q, J=8.1 Hz, J=2.7 Hz), 124.9 (q, J=5.8 Hz, J=3.8 Hz), 117.6(d, J=18.8 Hz), 106.3 (d, J=22.7 Hz), 74.8, 70.7, 56.1, 51.7, 41.5,32.3, 31.4, 25.5, 25.1, 24.3, 11.0.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.154 g). HPLC-MS(ammonium acetate) [M+H]⁺=367.25.

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(122LH11-1)

A reaction flask was charged with6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.183 g, 1.0 mmol)in dry DMF (1 mL) under Argon. NaH (60% in oil, 0.050 g, 1.3 mmol) wasadded and the mixture was stirred at rt for 0.5 h. Then(R,S)-1-bromo-3-chloro-2-methylpropane (0.172 g, 1.0 mmol) was addedfollowed by stirring at rt for 20 h. The reaction mixture was quenchedwith water, and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. Afterpurification by flash CC (SiO₂; EtOAc/n-heptane 1:1), the crude productwas solvated in DMF (0.5 mL) and added 4-butylpiperidine 0.085 g, 0.6mmol), NaI (0.113 g, 0.075 mmol), and K₂CO₃ (0.104 g, 0.075 mmol)followed by stirring at 50° for 3 days. The reaction mixture wasquenched with water, and the product extracted into EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by cation exchange CC and prep RP-HPLC togive the title compound (122LH11-1). ¹H NMR (CD₃OD) d 7.25-7.20 (m, 1H),7.16-7.12 (m, 1H), 3.97 (dd, J=14.3 Hz, J=8.4 Hz, 1H), 3.85 (dd, J=14.5Hz, J=5.1 Hz, 1H), 2.94-2.85 (m, 3H), 2.78 (d, J=9.4 Hz, 1H), 2.66-2.57(m, 2H), 2.27-2.13 (m, 2H), 2.03-1.85 (m, 3H), 1.67-1.65 (m, 2H),1.31-1.22 (m, 9H), 0.90 (t, J=6.6 Hz, CH₃), 0.87 (d, J=6.7 Hz, CH₃).

The crude product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.025 g, 7%). HPLC-MS(ammonium acetate) [M+H]⁺=379.27.

(R,S)-6,7-Difluoro-1-[3-(4-propoxypiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(122LH11-2)

A reaction flask was charged with6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.183 g, 1.0 mmol)in dry DMF (1 mL) under Argon. NaH (60% in oil, 0.050 g, 1.3 mmol) wasadded and the mixture was stirred at rt for 0.5 h. Then(R,S)-1-bromo-3-chloro-2-methylpropane (0.172 g, 1.0 mmol) was addedfollowed by stirring at rt for 20 h. The reaction mixture was quenchedwith water, and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. Afterpurification by flash CC (SiO₂; EtOAc/n-heptane 1:1), the crude productwas solvated in DMF (0.5 mL) and added 4-butylpiperidine 0.085 g, 0.6mmol), NaI (0.113 g, 0.075 mmol), and K₂CO₃ (0.104 g, 0.075 mmol)followed by stirring at 50° for 3 days. The reaction mixture wasquenched with water, and the product extracted into EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Thecrude product was purified by cation exchange CC and prep RP-HPLC togive the crude title compound (122LH11-2). ¹H NMR (CD₃OD) d 7.24-7.12(m, 2H), 3.97 (dd, J=14.5 Hz, J=8.6 Hz, 1H), 3.87 (dd, J=14.3 Hz, J=5.1Hz, 1H), 3.41 (t, J=6.7 Hz, CH₂), 3.35-3.28 (m, 1H), 2.89-2.85 (m, 2H),2.78-2.75 (m, 1H), 2.66-2.59 (m, 3H), 2.26-2.21 (m, 1H), 2.17-2.11 (m,2H), 2.07-1.97 (m, 2H), 1.90-1.86 (m, 2H), 1.61-1.51 (m, 4H), 0.92 (t,J=7.4 Hz, CH₃), 0.86 (d, J=6.6 Hz, CH₃); 13C NMR (CD₃OD) d 172.5, 150.3(q, J=242.9 Hz, J=13.1 Hz), 146.8 (q, J=243.3 Hz, J=13.1 Hz), 137.3 (q,J=8.1 Hz, J=2.7 Hz), 125.1 (q, J=5.8 Hz, J=3.8 Hz), 117.6 (d, J=18.8Hz), 106.7 (d, J=22.7 Hz), 76.3, 70.9, 64.5, 53.4, 52.8, 47.1, 32.5,32.4, 30.5, 25.5, 24.3, 17.2, 11.0.

The crude product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.030 g, 8%). HPLC-MS(ammonium acetate) [M+H]⁺=381.27.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one(107LH93-1)

A reaction flask was charged with6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) indry DMF (1 mL) under N₂. NaH (60% in oil, 0.038 g, 0.92 mmol) was addedand stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.131 g, 0.84mmol) was added followed by stirring at r.t for 20 h. The reactionmixture was quenched with water and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in MeCN (2 mL) followedby addition of 4-butylpiperidine (0.085 g, 0.6 mmol), NaI (0.150 g, 1.0mmol), and K₂CO₃ (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by cation exchange CC followed byflash CC (SiO₂; EtOAc) to give the title compound (107LH93-1) (0.166 g,total yield 55%). ¹H NMR (CH₃OD) δ 7.00 (d, J=6.4 Hz, 1H), 6.88 (d,J=9.2 Hz, 1H), 3.98-3.91 (m, 2H), 2.93-2.86 (m, 2H), 2.85-2.78 (m, 2H),2.58-2.52 (m, 2H), 2.40-2.43 (m, 2H), 2.25 (d, J=2.0 Hz, 3H), 1.98-1.76(m, 4H), 1.70-1.62 (m, 2H), 1.35-1.22 (m, 9H), 0.88 (t, J=7.0 Hz, 3H);¹³C NMR (CH₃OD) δ 171.1, 157.2 (d, J=241 Hz), 135.1 (d, J=3 Hz), 126.5(d, J=8 Hz), 123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz),55.8, 43.9, 40.4, 36.2, 35.7, 32.0, 31.5, 29.0, 24.6, 24.3, 22.8, 13.4(br).

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.172 g).HPLC-MS (ammonium acetate) [M+H]⁺=363.4.

6-Fluoro-7-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH93-2)

A reaction flask was charged with6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) indry DMF (1 mL) under N₂. NaH (60% in oil, 0.038 g, 0.92 mmol) was addedand stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.131 g, 0.84mmol) was added followed by stirring at r.t for 20 h. The reactionmixture was quenched with water and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in MeCN (2 mL) followedby addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), NaI (0.150 g,1.0 mmol), and K₂CO₃ (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h.The reaction mixture was quenched with water and the product extractedinto EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The residue was purified by cation exchangeCC followed by flash CC (SiO₂; EtOAc) to give the title compound(107LH93-2) (0.171 g, total yield 56%). ¹H NMR (CH₃OD) δ 7.00 (d, J=6.4Hz, 1H), 6.87 (d, J=9.2 Hz, 1H), 3.94 (brt, J=7.2 Hz, 2H), 3.39 (t,J=6.6 Hz, 2H), 3.35-3.26 (m, 1H), 2.85-2.70 (m, 4H), 2.58-2.51 (m, 2H),2.39 (brt, 7.4 Hz, 2H), 2.24 (d, J=1.6 Hz, 3H), 2.21-2.12 (m, 2H),1.92-1.75 (m, 4H), 1.62-1.48 (m, 4H), 0.91 (t, J=7.4 Hz); ¹³C NMR(CH₃OD) δ 171.0, 157.1 (d, J=241), 135.2 (d, J=3 Hz), 126.5 (d, J=8 Hz),123.2 (d, J=18 Hz), 118.1 (d, J=5 Hz), 114.3 (d, J=24 Hz), 74.6, 69.5,55.4, 51.0, 40.4, 31.5, 30.9, 24.7, 24.5, 23.2, 13.5 (br), 10.0.

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.172 g).HPLC-MS (ammonium acetate) [M+H]⁺=364.3.

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one(107LH94-1)

A reaction flask was charged with6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) indry DMF (1 mL) under N₂. NaH (60% in oil, 0.038 g, 0.92 mmol) was addedand stirred at rt for 30 min. Then(R,S)-1-bromo-3-chloro-2-methylpropane (0.144 g, 0.84 mmol) was addedfollowed by stirring at r.t for 20 h. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudematerial was dissolved in dry DMF (2 mL) followed by addition of4-butylpiperidine (0.085 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), andK₂CO₃ (0.138 g, 1.0 mmol) and shaken at 100° C. for 20 h. The reactionmixture was quenched with water and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by cation-exchange CC followed byflash CC (SiO₂; EtOAc) to give the title compound (107LH94-1) (0.045 g,total yield 14%). ¹H NMR (CH₃OD) δ 7.01 (d, J=6.4 Hz, 1H), 6.90 (d,J=9.2 Hz), 4.03-3.88 (m, 2H), 2.90 (brd, J=10.8 Hz, 2H), 2.83 (brt,J=7.0 Hz, 2H), 2.75 (brd, J=10.2 Hz), 2.64-2.50 (m, 2H), 2.26-1.98 (m,6H), 1.93-1.78 (m, 2H), 1.68-1.58 (m, 2H), 1.35-1.14 8 (m, 9H), 0.89 (t,J=6.8 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H); ¹³C NMR (CH₃OD) δ 171.6, 156.1(d, J=241 Hz), 135.1 (d, J=3 Hz), 126.9 (d, J=8 Hz), 123.0, (d, J=19Hz), 118.6 (d, J=5 Hz), 114.3 (d, J=24 Hz), 63.9, 55.1, 54.4, 45.5,36.3, 35.9, 32.4 (br), 31.6, 29.0, 28.8, 24.6, 22.8, 16.0, 13.5 (br).

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.037 g).HPLC-MS (ammonium acetate) [M+H]⁺=375.3.

(R,S)-6-Fluoro-7-methyl-1-[2-methyl-3-(4-propoxypiperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one(107LH94-2)

A reaction flask was charged with6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.150 g, 0.84 mmol) indry DMF (1 mL) under N₂. NaH (60% in oil, 0.038 g, 0.92 mmol) was addedand stirred at rt for 30 min. Then(R,S)-1-bromo-3-chloro-2-methylpropane (0.144 g, 0.84 mmol) was addedfollowed by stirring at r.t for 20 h. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The crudematerial was dissolved in dry DMF (2 mL) followed by addition of4-propoxypiperidine (0.086 g, 0.6 mmol), NaI (0.150 g, 1.0 mmol), andK₂CO₃ (0.138 g, 1.0 mmol) and shaken at 100° C. for 20 h. The reactionmixture was quenched with water and the product extracted into EtOAc.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by cation-exchange CC followed byflash CC (SiO₂; EtOAc) to give the title compound (107LH94-2) (0.033 g,total yield 10%). ¹H NMR (CH₃OD) δ 7.02 (d, J=6.8 Hz, 1H), 6.91 (d,J=9.6 Hz, 1H), 3.95 (d, J=7.2 Hz, 2H), 3.41 (t, J=6.6 Hz, 2H), 3.33-3.25(m, 1H), 2.84 (brt, J=7.4 Hz), 2.79-2.71 (m, 1H), 2.67-2.51 (m, 3H),2.28-1.98 (m, 8H), 1.92-1.83 (m, 2H), 1.60-1.48 (m, 4H), 0.91 (t, J=7.6Hz, 3H), 0.85 (d, J=6.4 Hz, 3H); ¹³C NMR (CH₃OD) δ 171.7, 157.2 (d,J=241 Hz), 135.1 (d, J=3 Hz), 126.9 (d, J=8 Hz), 123.1 (d, J=18 Hz),114.3 (d, J=24 Hz), 75.2, 69.5, 52.1, 51.7, 45.5, 31.6, 31.3, 29.0,24.6, 23.1, 15.9, 13.5, 13.3, 9.8.

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.036 g).HPLC-MS (ammonium acetate) [M+H]⁺=377.3.

1-[3-(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one(107LH95-1)

A reaction flask was charged with6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) indry DMF (0.5 mL) under N₂. NaH (60% in oil, 0.023 g, 0.55 mmol) wasadded and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.079g, 0.50 mmol) was added followed by stirring at r.t for 20 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in MeCN (2 mL) followedby addition of 4-butylpiperidine (0.085 g, 0.6 mmol), NaI (0.150 g, 1.0mmol), and K₂CO₃ (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by cation-exchange CC followed byflash CC (SiO₂; EtOAc) to give the title compound (107LH95-1) (0.059 g,total yield 33%). ¹H NMR (CH₃OD) δ 7.02 (dd, J=4.8, 9.2 Hz, 1H),6.98-6.92 (m, 1H), 3.95 (brt, J=7.4 Hz, 2H), 2.92-2.82 (m, 4H),2.59-2.52 (m, 2H), 2.39-2.32 (m, 2H), 2.00 (t, J=1.6 Hz, 3H), 1.97-1.75(m, 4H), 1.66 (brd, 10.8 Hz, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.4 Hz);¹³C NMR (CH₃OD) δ 170.9, 157.6 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1(d, J=4 Hz), 122.7 (d, J=18 Hz), 114.2 (d, J=8 Hz), 112.9, (d, J=25 Hz),55.9, 53.9, 40.6, 36.2, 35.7, 31.9, 30.9, 28.9, 24.4, 22.8, 21.4 (br),13.2, 9.7 (br).

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.058 g).HPLC-MS (ammonium acetate) [M+H]⁺=361.3.

6-Fluoro-5-methyl-1-[3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH95-2)

A reaction flask was charged with6-fluoro-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.090 g, 0.50 mmol) indry DMF (0.5 mL) under N₂. NaH (60% in oil, 0.023 g, 0.55 mmol) wasadded and stirred at rt for 30 min. Then 3-chloro-1-iodopropane (0.079g, 0.50 mmol) was added followed by stirring at r.t for 20 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude material was dissolved in MeCN (2 mL) followedby addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), NaI (0.150 g,1.0 mmol), and K₂CO₃ (0.138 g, 1.0 mmol) and shaken at 50° C. for 20 h.The reaction mixture was quenched with water and the product extractedinto EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The residue was purified by cation-exchangeCC followed by flash CC (SiO₂; EtOAc) to give the title compound(107LH95-2) (0.074 g, total yield 41%). ¹H NMR (CH₃OD) δ 7.03 (dd,J=4.8, 9.2 Hz, 1H), 6.99-6.92 (m, 1H), 3.98 (brt, J=7.4 Hz, 2H),3.46-3.38 (m, 3H), 2.95-2.84 (m, 4H), 2.64-2.42 (m, 6H), 2.20 (d, J=2.0Hz, 3H), 1.98-1.83 (m, 4H), 1.72-1.30 (m, 4H), 0.92 (t, J=7.4 Hz, 3H);¹³C NMR (CH₃OD) δ 171.1, 157.7 (d, J=240 Hz), 135.4 (d, J=3 Hz), 128.1(d, J=4 Hz), 122.8 (d, J=18 Hz), 114.1, (d, J=9 Hz), 113.0 (d, J=25 Hz),73.1, 69.7, 55.0, 50.3, 40.3, 30.8, 29.9, 23.9, 23.1, 22.7, 21.4, 9.8(br).

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.067 g).HPLC-MS (ammonium acetate) [M+H]⁺=363.3.

(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH47-A)

A 4 mL vial was charged with(S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18)(0.329 g, 1.0 mmol) and 4-butylpiperidine (0.283 g, 2.0 mmol) in MeCN (2mL) and shaken at 60° for 20 h. The reaction mixture was concentrated,and the product purified by flash CC (SiO₂; EtOAc, EtOAc/MeOH 4:1) togive the title compound (107LH47-A) (0.186 g, 54%). ¹H NMR (CD₃OD) d7.26-7.19 (M, 3H), 7.04-7.00 (m, 1H), 2.93-2.88 (m, 3H), 2.77 (d, J=10.4Hz, 2H), 2.62-2.58 (m, 2H), 2.29-2.06 (m, 3H), 1.93-1.86 (m, 2H),1.68-1.62 (m, 2H), 1.31-1.22 (m, 9H), 0.91-0.86 (m, 2 CH₃); ¹³C NMR(CD₃OD) d 173.2, 140.3, 129.1, 128.5, 128.4, 124.4, 166.9, 64.9, 56.0,55.6, 37.5, 36.9, 33.4, 33.3, 32.9, 30.1, 30.1, 26.2, 24.0, 17.2, 14.4.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.222 g). HPLC-MS(ammonium acetate) [M+H]⁺=343.33.

(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH48)

A 4 mL vial was charged with(S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18)(0.493 g, 1.5 mmol) and 4-propoxypiperidine (0.430 g, 3.0 mmol) in MeCN(2 mL) and shaken at 60° for 20 h. The reaction mixture was quenchedwith water, basified with ammonium hydroxide, and the product extractedinto EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash CC (SiO₂;EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH48) (0.197 g,38%). ¹H NMR (CD₃OD) d 7.26-7.19 (m, 3H), 7.03-6.98 (m, 1H), 3.96 (d,J=7.0 Hz, 2H), 3.40 (t, J=6.7 Hz, 2H), 2.90-2.86 (m, 2H), 2.74-2.71 (m,1H), 2.65-2.54 (m, 3H), 2.26-1.99 (m, 6H), 1.87-1.84 (m, 2H), 1.59-1.49(m, 4H), 0.91 (t, J=7.4 Hz, CH₃), 0.85 (d, J=6.6 Hz, CH₃); 13C NMR(CD₃OD) d 173.0, 140.3, 129.1, 128.4, 128.4, 124.3, 116.8, 76.3, 70.7,64.5, 53.2, 52.8, 32.9, 32.4, 32.4, 30.3, 26.2, 24.3, 17.1, 11.0.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.189 g). HPLC-MS(ammonium acetate) [M+H]⁺=345.31.

(R)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH53)

A 4 mL vial was charged with(S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18)(0.169 g, 0.51 mmol) and 4-butylidenepiperidine (0.200 g, 1.4 mmol) inMeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture wasquenched with water, basified with ammonium hydroxide, and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flash CC(SiO₂; n-heptane/EtOAc 4:1) to give the title compound (107LH53) (0.116g, 67%). ¹H NMR (CD₃OD) d 7.23-7.18 (m, 3H), 7.02-6.98 (m, 1H), 5.11 (t,J=7.4 Hz, 1H), 3.98 (d, J=6.8 Hz, 2H), 2.89-2.85 (m, 2H), 2.61-2.56 (m,2H), 2.40-2.35 (m, 2H), 3.32-2.04 (m, 11H), 1.98-1.92 (m, 2H), 1.36-1.29(m, 2H), 0.90-0.85 (m, 2 CH₃); ¹³C NMR (CD₃OD) d 173.0, 140.3, 137.1,129.1, 128.4, 128.4, 124.3, 123.7, 116.9, 64.6, 57.4, 56.6, 46.5, 37.0,32.9, 30.2, 30.1, 29.1, 26.3, 24.2, 17.2, 14.1.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.130 g). HPLC-MS(ammonium acetate) [M+H]⁺=341.33.

(R)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH54)

A 4 mL vial was charged with(S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18)(0.185 g, 0.56 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.100 g,0.60 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reactionmixture was quenched with water, basified with ammonium hydroxide, andthe product extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified byflash CC (SiO₂; n-heptane/EtOAc 4:1) to give the title compound(107LH54) (0.063 g, 30%). ¹H NMR (CD₃OD) d 7.29-7.19 (m, 3H), 7.03-6.99(m, 1H), 4.03-4.00 (m, 2H), 3.14-3.13 (m, 1H), 3.07-3.05 (m, 1H),2.90-2.86 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.19 (m, 2H), 1.97-1.82 (m,3), 1.58-1.42 (m, 5H), 1.34-1.15 (m, 8H), 0.90-0.87 (m, 6H); ¹³C NMR(CD₃OD) d 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.2, 62.2, 61.2,58.2, 46.5, 39.0, 38.0, 32.9, 32.1, 30.3, 29.1, 27.8, 27.3, 26.3, 24.0,17.1, 14.5.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.064 g). HPLC-MS(ammonium acetate) [M+H]⁺=369.34.

(R)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH55)

A 4 mL vial was charged with(S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18)(0.185 g, 0.56 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.112 g,0.62 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reactionmixture was quenched with water, basified with ammonium hydroxide, andthe product extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified byflash CC (SiO₂; n-heptane/EtOAc 4:1) to give the title compound(107LH55) (0.075 g, 35%). ¹H NMR (CD₃OD) d 7.28-7.18 (m, 3H), 7.01 (t,J=7.2 Hz, 1H), 4.03 (d, J=7.0 Hz, 2H), 3.11-3.04 (m, 2H), 2.90-2.85 (m,2), 2.64-2.56 (m, 2H), 2.28-2.11 (m, 4H), 1.97-1.84 (m, 3H), 1.66-1.54(m, 3H), 1.42-1.21 (m 10H), 0.09-0.85 (m, 2 CH₃); ¹³C NMR (CD₃OD) d173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.1, 61.4, 60.2, 58.3, 46.4,39.5, 37.1, 37.0, 33.1, 32.9, 32.2, 29.5, 29.4, 28.5, 27.9, 26.3, 23.7,17.1, 14.4.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.054 g). HPLC-MS(ammonium acetate) [M+H]⁺=383.35.

1-[3-(4-Butylpiperidin-1-yl)propyl]-1H-quinolin-2-one (092LH70-A)

A 7mL vial was charged with l-(3-chloropropyl)-1H-quinolin-2-one (0.450g, 2.0 mmol), K₂CO₃ (0.34 g, 2.5 mmol), KI (0.42 g, 2.5 mmol),4-butylpiperidine (0.30 g, 2.1 mmol) and dry CH₃CN (3 mL). The mixturewas shaken at 50° C. for 60 h and thereafter diluted with EtOAc (50 mL)and washed with water (50 mL). The water phase was extracted with EtOAc(2×50 mL). The combined organic phase was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byflash CC (SiO₂; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give thetitle compound (0.32 g, 49%). ¹H NMR (CD₃OD) δ 7.88 (d, J=9.6 Hz), 7.68(brd, J=8.0 Hz), 7.65-7.61 (m, 2H), 7.33-7.25 (m, 1H), 6.64 (d, 9.6 Hz),4.39-4.32 (m, 2H), 2.95-2.86 (m, 2H), 2.50-2.43 (m, 2H), 2.01-1.86 (m,4H), 1.71-1.62 (m, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.6 Hz); ¹³C NMR(CD₃OD) δ 163.1, 140.4, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7,55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.7, 22.8, 13.2.

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.356 g).HPLC-MS (ammonium acetate) [M+H]⁺=327.3.

1-[3-(4-Propoxypiperidin-1-yl)propyl]-1H-quinolin-2-one (092LH69)

A 4 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.069g, 0.31 mmol), K₂CO₃ (0.069 g, 0.50 mmol), KI (0.083 g, 0.50 mmol),4-propoxypiperidine (0.050 g, 0.35 mmol) and dry CH₃CN (2 mL). Themixture was shaken at 50° C. for 24 h and thereafter diluted with water(25 mL) and EtOAc (25 mL). The phases were separated and the water phasewas extracted with EtOAc (2×50 mL). The combined organic phase was thendried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash CC (SiO₂; EtOAc/MeOH 4:1) followed byprep RP-HPLC to give the title compound (0.060 g, 59%). ¹H NMR (CD₃OD) δ7.85 (d, J=9.4 Hz, 1H), 7.65 (brd, J=7.2 Hz, 1H), 7.63 (m, 2H),7.29-7.22 (m, 1H), 6.62, (d, J=9.4 Hz), 4.36-4.29 (m, 1H), 3.38 (t,J=6.6 Hz, 2H), 3.34-3.24 (m, 1H), 2.78-2.69 (m, 2H), 2.48-2.41 (m, 2H),2.18-2.09 (m, 2H), 1.94-1.82 (m, 4H), 1.59-1.47 (m, 4H), 0.90 (t, J=7.4Hz); ¹³C NMR (CD₃OD) δ 162.0, 140.3, 139.0, 131.1, 129.2, 122.6, 121.4,120.3, 114.7, 74.7, 69.5, 55.4, 51.0, 40.6, 31.0, 24.9, 32.1, 9.9;HPLC-MS (ammonium acetate) [M+H]⁺=329.3.

1-[3-(4-Butylipiperidin-1-yl)propyl]-6-fluoro-1H-quinolin-2-one(107LH22)

A 4 mL vial was charged with 6-fluoro-1H-quinolin-2-one (00.56 g, 0.34mmol), dry DMF (2 mL) and NaH (60% in oil, 0.015 g, 0.34 mmol). Themixture was stirred at rt for 1 h under a N₂ atmosphere, and thereafter1-bromo-3-chloropropane (34 μl, 0.34 mmol) was added and the mixture wasthen shaken at rt for 20 h. The reaction was diluted with diethyl ether(25 mL) and washed with water (15 mL). The organic phase was washed withwater (15 mL) and brine (15 mL), dried over Na₂SO₄, and concentratedunder reduced pressure. The oily residue was diluted with CH₃CN (2 mL)and KI (0.083 g, 0.50 mmol), K₂CO₃ (0.069 g, 0.50 mmol) and4-butylpiperidine (0.048 g, 0.34 mmol) was added. The mixture was shakenat 50° C. for 72 h and then diluted with EtOAc (25 mL) and washed withwater (15 mL). The water phase was extracted (2×25 mL) and the combinedorganic phase was dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by cation-exchange CC followed byflash CC (SiO₂; EtOAc/MeOH 4:1) to yield the title compound (0.034 g,29%). ¹H NMR (CD₃OD) δ 7.90 (d, J=9.2 Hz, 1H), 7.69 (dd, J=4.0, 8.8 Hz,1H), 7.50-7.41 (m, 2H), 6.72 (d, J=8.8 Hz, 1H), 4.41 (t, J=6.8 Hz, 2H),3.02-2.95 (m, 2H), 2.65-2.60 (m, 2H), 2.19-2.08 (m, 2H), 1.91-1.82 (m,4H), 1.53-1.53-1.21 (m, 9H), 0.90 (t, J=7.0 Hz); ¹³C NMR (CD₃OD) δ169.9, 158.4 (d, J=242 Hz), 139.8 (d, J=3 Hz), 134.4 (d, J=2 Hz), 122.5(d, J=9 Hz), 121.6, 119.9 (d, J=24 Hz), 116.8 (d, J=8 Hz), 113.9 (d=23Hz), 54.4, 53.0, 40.1, 34.5, 34.1, 30.1, 28.7, 23.3, 22.6, 13.2; HPLC-MS(ammonium acetate) [M+H]⁺=345.3.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-1H-quinolin-2-one(107LH32-A)

A 4 mL vial was charged with 6-methyl-1H-quinolin-2-one (0.110 g, 0.71mmol), dry DMF (2 mL) and NaH (60% in oil, 0.031 g, 0.78 mmol). Themixture was shaken under a N₂ atmosphere for 1 h, and thereafter1-bromo-3-chloropropane (70 μl, 0.71 mmol) was added. The reaction wasshaken at rt for 20 h and then poured into diethyl ether (25 mL) andwashed with water (15 mL). The ether phase was washed with water (15 mL)and brine (15 mL). The organic phase was dried over Na₂SO₄, andconcentrated under reduced pressure. The residue was diluted with CH₃CN(2 mL) and KI (0.160 g, 1.0 mmol), K₂CO₃ (0.140 g, 1.0 mmol) and4-butylpiperidine (0.100 g, 0.71 mmol) was added. The mixture was shakenat 50° C. for 72 h and then poured onto The compound EtOAc (25 mL) andwater (15 mL). The water phase was extracted (2×25 mL) and the combinedorganic phase was dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by flash CC (SiO₂; EtOAc/MeOH 4:1)followed by prep RP-HPLC to give the title compound (0.058 g, 23%). ¹HNMR (CD₃OD) δ 7.78 (d, J=9.2 Hz, 1H), 7.52-7.40 (m, 3H), 6.60 (d, J=9.2Hz, 1H), 4.3 (t, J=7.6 Hz, 2H), 2.92-2.2.85 (m, 2H), 2.50-2.39 (m, 2H),2.39 (s, 3H), 1.99-1.84 (m, 4H), 1.69-1.61 (m, 2H), 1.35-1.11 (m, 9H),0.88 (t, J=6.8 Hz); ¹³C NMR (CD₃OD) δ 162.9, 140.1, 137.0, 132.5, 132.3,128.8, 121.4, 120.2, 114.6, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9,24.8, 22.8, 19.4, 13.3; HPLC-MS (ammonium acetate) [M+H]⁺=341.3.

1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-1H-quinolin-2-one(107LH33-A)

A 4 mL vial was charged with 7-fluoro-1H-quinolin-2-one (0.032 g, 0.19mmol), NaH (60% in oil, 8.7 mg, 0.21 mmol) and dry DMF (2.5 mL). Themixture was shaken at rt for 1 h and then 1-bromo-3-chloropropane (20μl, 0.19 mmol) was added and the reaction was shaken overnight shaken atrt overnight. The mixture was then diluted with ether (25 mL) and washedwater (15 mL), the ether phase was washed with water (15 mL) and brine(15 mL). The organic phase was dried over Na₂SO₄, and concentrated underreduced pressure. The oily residue was diluted with CH₃CN (2 mL) and tothe resulting solution was added: KI (0.050 g, 0.30 mmol), K₂CO₃ (0.041g, 0.30 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol). The mixturewas shaken at 50° C. for 72 h and then poured onto The compound EtOAc(25 mL) and water (15 mL). The water phase was extracted (2×25 mL) andthe combined organic phase was dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by flash CC (SiO₂; EtOAc/MeOH4:1) followed by prep RP-HPLC to give the title compound (7.0 mg, 11%).¹H NMR (CD₃OD) δ 7.89 (d, J=9.6 Hz, 1H), 7.73 (dd, J=6.2, 8.6 Hz, 1H),7.47 (dd, J=2.4, 11.6 Hz, 1H), 7.08 (dt, J=2.4, 8.6 Hz, 1H), 6.60 (dJ=9.6 Hz, 1H), 4.33 (t, J=7.6 Hz, 2H), 2.98-2.00 (m, 2H), 2.50-2.42 (m,2H), 2.05-1.86 (m, 4H), 1.55-1.64 (m, 2H), 1.36-1.15 (m, 9H), 0.90 (t,J=6.8 Hz); ¹³C NMR (CD₃OD) δ 164.7 (d, J=248), 163.2, 140.9 (br), 139.9,131.4 (d, J=10 Hz), 119.3 (d, J=3 Hz), 118.1 (br), 110.6 (d, J=23 Hz),101.6 (d, J=28 Hz), 55.5, 53.9, 41.0, 36.8, 35.6, 31.9, 28.9, 24.5,22.7, 13.2; HPLC-MS (ammonium acetate) [M+H]⁺=345.3

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methoxy-1H-quinolin-2-one(107LH37-A)

A 4 mL vial was charged with 6-methoxy-1H-quinolin-2-one (0.032 g, 0.18mmol) dry DMF (2 mL) and NaH (60% in oil, 8 mg, 0.20 mmol), thereafterthe mixture was stirred at 45° C. for 45 min under a N₂ atmosphere,followed by the addition of 1-bromo-3-chloropropane (18 μl, 0.18 mmol)and the mixture was shaken at 30° C. overnight. The reaction was thendiluted with ether (25 mL) and washed with water (15 mL) and brine (15mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theoily residue was diluted with CH₃CN (3 mL) and KI (0.080 g, 0.50 mmol),K₂CO₃ (0.070 g, 0.50 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol)were added. The mixture was shaken at 50° C. for 48 h and then dilutedwith EtOAc (25 mL) and washed with water (15 mL). The water phase wasextracted (2×25 mL) and the combined organic phase was dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by prep RP-HPLC to give the title compound (0.028 g, 44%). ¹HNMR (CD₃OD) δ 7.85 (d, J=9.6 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.26 (dd,J=2.8, 9.6 Hz, 1H), 7.19 (d J=2.8 Hz, 1H), 6.65 (d, J=9.6 Hz, 1H), 4.34(t, J=7.2 Hz, 2H), 3.85 (s, 3H), 3.07-2.98 (m, 2H), 2.64-2.58 (m, 2H),2.19-2.10 (m, 2H), 2.04-1.94 (m, 2H), 1.76-1.66 (m, 2H), 1.35-0.96 (m,9H), 0.89 (t, J=6.8 Hz.); ¹³C NMR (CD₃OD) δ 162.7, 155.5, 140.1, 133.3,122.3, 120.6, 120.1, 116.1, 110.5, 55.3, 55.0, 53.6, 40.5, 36.0, 35.2,31.4, 28.8 24.4, 22.7, 13.2; HPLC-MS (ammonium acetate) [M+H]⁺=357.3.

1-[3-(4-Butylpiperidin-1-yl)propyl]-6-chloro-1H-quinolin-2-one(107LH38-A)

A 4 mL vial was charged with 6-chloro-1H-quinolin-2-one (107LH35) (0.085g, 0.47 mmol), dry DMF (3 mL) and NaH (60% in oil, 0.023 g, 0.56 mmol)and the mixture was stirred at rt for 45 min under a N₂ atmosphere.Thereafter, 1-bromo-3-chloropropane (18 μl, 0.18 mmol) was added and themixture was shaken at rt overnight, the reaction diluted with ether (25mL) and washed with water (15 mL). The ether phase was washed with brine(15 mL), dried over Na₂SO₄, concentrated under reduced pressure. Theoily residue was diluted with dry CH₃CN (2 mL) and KI (0.170 g, 1.0mmol), K₂CO₃ (0.140 g, 1.0 mmol) and 4-butylpiperidine (0.071 g, 0.50mmol) were added. The mixture was shaken at 50° C. for 24 h and thendiluted with EtOAc (25 mL) and washed with water (15 mL). The waterphase was extracted (2×25 mL) and the combined organic phases were driedover Na₂SO₄, and concentrated under reduced pressure. The residue waspurified by prep RP-HPLC to give the title compound (32 mg, 89 μmol,19%). ¹H NMR (CD₃OD) δ 7.80 (d, J=9.2Hz, 1H), 7.66 (brs, 1H), 7.60-7.51(m, 2H), 6.65 (d, J=9.6 Hz, 1H), 5.30 (t, J=7.6 Hz, 2H), 3.09-2.95 (m,2H), 2.68-2.57 (m, 2H), 2.24-2.06 (m 2H), 2.00-1.90 (m, 2H), 1.75-1.64(m, 2H), 1.32-1.12 (m, 9H), 0.84 (t, 6.4 Hz, 3H); ¹³C NMR (CD₃OD) δ162.6, 139.2, 137.4, 130.8, 128.0, 127.8, 122.4, 121.5, 116.3, 55.0,53.3, 40.3, 35.7, 34.8, 31.0, 28.6, 23.9, 22.5, 13.0; HPLC-MS (ammoniumacetate) [M+H]⁺=361.3.

1-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-1H-quinolin-2-one (107LH45)

A 4 mL vial was charged with1-(3-chloropropyl)-5-methyl-1H-quinolin-2-one (0.053 g, 0.23 mmol), KI(0.083 g, 0.5 mmol), K₂CO₃ (0.069 g, 0.50 mmol) and 4-butylpiperidine(50 μl, 0.30 mmol) in CH₃CN (2 mL). The mixture was shaken at 50° C. for72 h and then diluted with EtOAc (25 mL) and washed with water (15 mL).The water phase was extracted (2×25 mL) and the combined organic phaseswere dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by flash CC (SiO₂; EtOAc/MeOH 1:4) to give thetitle compound (0.058 g, 74%). ¹H NMR (CD₃OD) δ 8.13 (d, J=9.8 Hz, 1H),7.56-7.46 (m, 2H), 7.15 (brd, 6.8 Hz, 2H), 6.67 (d, J=9.8 Hz, 1H), 4.38(t, J=7.2 Hz, 2H), 3.10-3.03 (m, 2H), 2.68-2.61 (m, 2H), 2.57 (s, 3H),2.25-2.15 (m, 2H), 2.04-1.95 (m, 2H), 1.78-1.69 (m, 2H), 1.36-1.16 (m,9H), 0.89 (t, J=7.0 Hz, 3H); ¹³C NMR (CD₃OD) δ 162.3, 138.7, 136.6,136.2, 130.4, 123.6, 119.4, 118.9, 112.4, 54.7, 52.9, 39.9, 35.3, 34.5,30.7, 28.2, 23.7, 22.1, 17.3, 12.6; HPLC-MS (ammonium acetate)[M+H]⁺=341.3.

1-[3-(4-Butyl-piperidin-1-yl)propyl]-7-methyl-1H-quinolin-2-one(107LH46-A)

A 4 mL vial was charged with1-(3-chloro-propyl)-7-methyl-1H-quinolin-2-one 107LH40 (0.130 g, 0.56mmol), KI (0.170 g, 1.0 mmol), K₂CO₃ (0.140 g, 1.0 mmol) and4-butylpiperidine (100 μl, 0.60 mmol) in CH₃CN (2 mL). The mixture wasshaken at 50° C. for 72 h and then poured onto The compound EtOAc (25mL) and water (15 mL). The water phase was extracted (2×25 mL) and thecombined organic phases were dried over Na₂SO₄, and concentrated underreduced pressure. The residue was purified by flash CC (SiO₂; EtOAc/MeOH1:4) to give the title compound (0.017 g, 6%). ¹H NMR (CD₃OD) δ 7.84 (d,J=9.4 Hz), 7.56 (d, J=8.0 Hz, 1H), 7.43 (brs, 1H), 7.14 (brd, J=8 Hz,1H), 6.58 (d, J=9.4 Hz), 4.36 (d, J=7.2 Hz, 2H), 3.02-2.95 (m, 2H),2.57-2.48 (m, 2H), 2.51 (s, 3H), 2.09-1.91 (m, 4H), 1.75-1.65 (m, 2H9,1.36-1.16 (m, 9H), 0.89 (t, J=6.8 Hz, 3H); ¹³C NMR (CD₃OD) δ 163.3,142.2, 140.3, 139.1, 129.1, 124.1, 119.3, 119.0, 114.7, 55.6, 53.8,40.4, 36.1, 35.5, 31.8, 28.9, 24.6, 22.7, 21.1, 13.2; HPLC-MS (ammoniumacetate) [M+H]⁺=341.3.

(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-1H-quinolin-2-one(107LH52)

A 4mL vial was charged with crude(S)-1-(3-iodo-2-methyl-propyl)-1H-quinolin-2-one (0.66 g),4-butylpiperidine (0.43 g, 3.0 mmol) and dry CH₃CN (1 mL). The mixturewas shaken at 50° C. for 72 h and then poured onto The compound EtOAc(50 mL) and water (25 mL). The water phase was extracted (2×25 mL) andthe combined organic phases were dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by flash CC (SiO₂;EtOAc/MeOH 1:4) and then cation-exchange CC producing the title compound(0.300 g, 44%). ¹H NMR (CD₃OD) δ 7.88 (d, J=9.2 Hz, 1H), 7.73-7.66 (m,2H), 7.61 (t, J=8.0 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 6.65 (d, J=9.2 Hz,1H), 4.42-4.26 (m, 2H), 2.90 (brd, J=11.4 Hz, 1H), 2.74 (brd, J=11.4 Hz,1H), 2.40-2.16 (m, 3), 1.94-1.78 (m, 2H), 1.64-1.54 (m, 2H), 1.35-1.00(m, 9H), 0.96-0.85 (m, 6H); ¹³C NMR (CD₃OD) δ 163.7, 140.2, 139.5,130.8, 129.1, 122.5, 121.4, 120.4, 115.3, 64.0, 55.1, 54.2, 46.8, 36.3,35.8, 32.4, 32.3, 29.8, 28.9, 22.8, 16.1, 13.2.

The product was dissolved in acetone and tartric acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.277 g).HPLC-MS (ammonium acetate) [M+H]⁺=341.3.

(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-1H-quinolin-2-one(107LH65)

A 4 mL vial was charged with crude(S)-1-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g),4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH₃CN (2.5 mL). Themixture was shaken at 50° C. for 24 h and then purified bycation-exchange CC followed by flash CC (SiO₂; EtOAc/MeOH 1:4) to givethe title compound (0.051 g, 17%). ¹H NMR (CD₃OD) δ 7.85 (d, J=9.6 Hz),7.70-7.63 (m, 2H), 7.60 (brt, J=7.8 Hz, 1H), 7.26 (brt, 7.6 Hz), 6.63(d, J=9.6 Hz, 1H), 4.39-4.23 (m, 2H), 3.37 (t, J=6.6 Hz), 3.28-3.18 (m,1H), 2.77-2.69 (m, 1H), 2.64-2.58 (m, 1H), 2.35 (dd, J=8.4, 12.0 Hz),2.51-2.21 (m, 1H), 2.18 (dd, J=4.8, 12.0 Hz), 2.13-2.04 (m, 1H),2.00-1.92 (m, 1H), 1.84-1.75 (m, 2H), 1.58-1.32 (m, 4H), 0.95-0.85 (m,6H); ¹³C NMR (CD₃OD) δ 163.7, 140.2, 139.5, 130.8, 129.2, 12.5, 121.4,120.4, 115.2, 75.3, 69.5, 63.6, 52.3, 51.5, 46.8, 31.4, 31.3, 30.0,23.1, 16.1, 9.8.

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.032 g).HPLC-MS (ammonium acetate) [M+H]⁺=343.3.

1-[3-(4-Allyloxypiperidin-1-yl)propyl]-1H-quinolin-2-one (107LH85)

A 4 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.130g, 0.6 mmol), NaI (0.225 g, 1.5 mmol), K₂CO₃ (0.210 g, 1.5 mmol),4-allyloxypiperidine (0.085 g, 0.60 mmol) and dry CH₃CN (1 mL). Themixture was shaken at 40° C. for 72 h and then poured onto The compoundEtOAc (25 mL) and water (15 mL). The water phase was extracted (2×25 mL)and the combined organic phases were dried over Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by flash CC (SiO₂;EtOAc/MeOH 4:1) followed by cation-exchange CC to yield the titlecompound (0.140 g, 70%). ¹H NMR (CD₃OD) δ 7.81 (d, J=9.6 Hz, 1H),7.64-7.55 (m, 3H), 7.27-7.21 (m, 1H), 6.61 (d, J=9.6 Hz, 1H), 5.93-5.82(m, 1H), 5.27-5.20 (m, 1H), 5.13-5.07 (m, 1H), 4.33-4.26 (m, 2H),3.40-3.28 (m, 2H), 2.76-2.67 (m, 2H), 2.47-2.39 (m, 2H), 2.18-2.08 (m,1H), 1.93-1.80 (m, 4H), 1.61-1.50 (m, 2H); ¹³C NMR (CD₃OD) δ 162.9,140.3, 139.0, 135.5, 131.1, 129.2, 122.6, 121.3, 120.4, 115.5, 114.7,74.2, 68.7, 55.3, 51.0, 40.6, 30.9, 24.9.

The product was dissolved in acetone and oxalic acid (1.1 equiv)dissolved in acetone was added. The formed crystals were filtered andwashed with acetone to give the title compound as oxalic salt (0.140 g).HPLC-MS (ammonium acetate) [M+H]⁺=327.3.

General Procedure 18 (GP18)

A 7 mL vial was charged with heterocycle (1 equiv),(R,S)-1-bromo-3-chloro-2-methylpropane (1.2 equiv), and Cs₂CO₃ (2 equiv)in MeCN (4 mL) and stirred at 50° for 20 h. The reaction mixture wasadded water, and the product extracted into EtOAc. The combined organiclayers were filtered through a PTFF filter and concentrated. The productwas used for the next reaction step without further purification.

(R,S)-4-(3-Chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a)

6-Methyl-4H-benzo[1,4]oxazin-3-one (0.512 g, 3.14 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.646 g, 3.77 mmol), and Cs₂CO₃(2.036 g, 6.25 mmol) in MeCN (4 mL) were reacted and worked up accordingto GP18 to give the crude title compound (112KK19-a) (0.692 g).

(R,S)-4-(3-Chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b)

6-Fluoro-4H-benzo[1,4]oxazin-3-one (0.502 g, 3.00 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.617 g, 3.60 mmol), and Cs₂CO₃(1.983 g, 6.09 mmol) in MeCN (4 mL) were reacted and worked up accordingto GP18 to give the crude title compound (112KK19-b) (0.768 g).

(R,S)-4-(3-Chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c)

7-Fluoro-4H-benzo[1,4]oxazin-3-one (0.498 g, 2.98 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.613 g, 3.58 mmol), and Cs₂CO₃(1.985 g, 6.09 mmol) in MeCN (4 mL) were reacted and worked up accordingto GP18 to give the crude title compound (112KK19-c) (0.694 g).

(R,S)-3-(3-Chloro-2-methylpropyl)-3H-benzothiazol-2-one (112KK19-d)

Benzothiazol-2-ol (0.476 g, 3.15 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.648 g, 3.78 mmol), and Cs₂CO₃(2.024 g, 6.21 mmol) in MeCN (4 mL) were reacted and worked up accordingto GP18 to give the crude title compound (112KK19-d) (0.804 g).

General Procedure 19 (GP19)

A 7 mL vial was charged with heterocycle (1 equiv),(R,S)-1-bromo-3-chloro-2-methylpropane (1 equiv), and Cs₂CO₃ (1.5 equiv)in MeCN (3 mL) and stirred at 50° for 20 h. The reaction mixture wasadded water and the product extracted into EtOAc. The combined org.layers were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash CC (SiO₂; EtOAc/n-heptane 1:1).

(R,S)-4-(3-Chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (107LH61-1)

4H-benzo[1,4]oxazin-2-one (0.447 g, 3.0 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and Cs₂CO₃(1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified accordingto GP19 to give the crude title compound (107LH61-1) (0.595 g).

(R,S)-4-(3-Chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one (107LH61-2)

4H-Benzo[1.4]thiazin-3-one (0.496 g, 3.0 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and Cs₂CO₃(1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified accordingto GP19 to give the crude title compound (107LH61-2) (0.593 g).

(R,S)-4-(3-Chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69)

6-Methoxy-4H-benzo[1,4]oxazin-3-one (111MF24) (0.538 g, 3.0 mmol),(R,S)-1-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and Cs₂CO₃(1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified accordingto GP19 to give the crude title compound (107LH69) (0.658 g).

(R,S)-1-(3-Chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63)

A reaction flask was charged with 3,4-dihydro-1H-quinolin-2-one (1.00 g,6.8 mmol) in dry DMF (10 mL). NaH 60% (0.300 g, 7.5 mmol) was added andthe mixture was stirred at rt for 1 h under an Argon atmosphere. Then(R,S)-1-bromo-3-chlor-2-methylpropane (1.165 g, 6.8 mmol) was addedfollowed by stirring at rt for 20 h. The crude product was concentratedand purified by flash CC (SiO₂; EtOAc/n-heptane 1:1) to give the crudetitle compound (107LH63) (0.753 g)

General Procedure 20 (GP20)

A 4 mL vial was charged with crude heterocycle, amine, NaI (0.100 g,0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF and stirred at 100°for 5 days. The reaction mixture was added water and the productextracted into EtOAc. The crude product was purified by cation exchangeCC and then prep. RP-HPLC to give the title compound.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a1)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a) (0.046 g), 4-butylpiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-a1) (0.007 g). HPLC-MS (ammonium acetate) [M+H]⁺=359.32.

(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a2)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a) (0.046 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-a2) (0.010 g). HPLC-MS (ammonium acetate) [M+H]⁺=361.29.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a3)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a) (0.046 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-a3) (0.008 g). HPLC-MS (ammonium acetate) [M+H]⁺=357.30.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a4)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a) (0.023 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-a4) (0.007 g). HPLC-MS (ammonium acetate)[M+H]⁺=385.32.

(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a5)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK19-a) (0.023 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-a5) (0.002 g). HPLC-MS (ammonium acetate)[M+H]⁺=399.35.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-b1)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b) (0.051 g), 4-butylpiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-b1) (0.011 g). HPLC-MS (ammonium acetate) [M+H]⁺=363.28.

(R,S)-6-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(112KK20-b2)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b) (0.051 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-b2) (0.010 g). HPLC-MS (ammonium acetate) [M+H]⁺=365.26.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-b3)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b) (0.051 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-b3) (0.011 g). HPLC-MS (ammonium acetate) [M+H]⁺=361.27.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-b4)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b) (0.026 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-b4) (0.009 g). HPLC-MS (ammonium acetate)[M+H]⁺=389.30.

(R,S)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-ylpropyl]-4H-benzo[1,4]oxazin-3-one(112KK20-b5)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-b) (0.026 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-b5) (0.009 g). HPLC-MS (ammonium acetate)[M+H]⁺=403.31.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-c1)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c) (0.046 g), 4-butylpiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-c1) (0.002 g). HPLC-MS (ammonium acetate) [M+H]⁺=363.29.

(R,S)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(112KK20-c2)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c) (0.046 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-c2) (0.002 g). HPLC-MS (ammonium acetate) [M+H]⁺=365.28.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-c3)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c) (0.046 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-c3) (0.008 g). HPLC-MS (ammonium acetate) [M+H]⁺=361.29.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK20-c4)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c) (0.023 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol) (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.2mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-c4) (0.004 g). HPLC-MS (ammonium acetate)[M+H]⁺=389.31.

(R,S)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one(112KK20-c5)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c) (0.023 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-c5) (0.002 g). HPLC-MS (ammonium acetate)[M+H]⁺=403.32.

(R,S)-3-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one(112KK20-d1)

Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d) (0.054 g), 4-butylpiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-d1) (0.012 g). HPLC-MS (ammonium acetate) [M+H]⁺=347.28.

(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3H-benzothiazol-2-one(112KK20-d2)

Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d) (0.054 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-d2) (0.011 g). HPLC-MS (ammonium acetate) [M+H]⁺=349.25.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3H-benzothiazol-2-one(112KK20-d3)

Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d) (0.054 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1.4 mL)were reacted and purified according to GP20 to give the title compound(112KK20-d3) (0.011 g). HPLC-MS (ammonium acetate) [M+H]⁺=345.27.

(R,S)-3-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3H-benzothiazol-3-one(112KK20-d4)

Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d) (0.027 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-d4) (0.011 g). HPLC-MS (ammonium acetate)[M+H]⁺=373.30.

(R,S)-3-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3H-benzothiazol-2-one(112KK20-d5)

Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d) (0.027 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1.2 mL) were reacted and purified according to GP20 to give the titlecompound (112KK20-d5) (0.011 g). HPLC-MS (ammonium acetate)[M+H]⁺=387.30.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(107LH74-a1)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(107LH61-1) (0.149 g), 4-butylpiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-a1) (0.092 g). HPLC-MS (ammonium acetate) [M+H]⁺=345.30.

(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one(107LH74-a2)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(107LH61-1) (0.149 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-a2) (0.077 g). HPLC-MS (ammonium acetate) [M+H]⁺=347.30.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(107LH74-a3)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(107LH61-1) (0.149 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-a3) (0.083 g). HPLC-MS (ammonium acetate) [M+H]⁺=343.30.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(107LH74-a4)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(107LH61-1) (0.074 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-a4) (0.046 g). HPLC-MS (ammonium acetate)[M+H]⁺=371.33.

(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one(107LH74-a5)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one(107LH61-1) (0.074 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-a5) (0.053 g). HPLC-MS (ammonium acetate)[M+H]⁺=385.34.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(107LH74-b1)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one(107LH61-2) (0.148 g), 4-butylpiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-b1) (0.083 g). HPLC-MS (ammonium acetate) [M+H]⁺=361.29.

(R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one(107LH74-b2)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one(107LH61-2) (0.148 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-b2) (0.071 g). HPLC-MS (ammonium acetate) [M+H]⁺=363.27.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(107LH74-b3)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one(107LH61-2) (0.148 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-b3) (0.064 g). HPLC-MS (ammonium acetate) [M+H]⁺=359.27.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(107LH74-b4)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one(107LH61-2) (0.074 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-b4) (0.040 g). HPLC-MS (ammonium acetate)[M+H]⁺=387.30.

(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one(107LH74-b5)

Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]thiazin-3-one(107LH61-2) (0.074 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-b5) (0.040 g). HPLC-MS (ammonium acetate)[M+H]⁺=401.30.

(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH74-c1)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63) (0.188 g), 4-butylpiperidine (0.042 g, 0.30 mmol), NaI (0.100g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) were reactedand purified according to GP20 to give the title compound (107LH74-cl)(0.047 g). HPLC-MS (ammonium acetate) [M+H]⁺=343.32.

(R,S)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3.4-dihydro-1H-quinolin-2-one(107LH74-c2)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63) (0.188 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-c2) (0.040 g). HPLC-MS (ammonium acetate) [M+H]⁺=345.32.

(R,S)-1-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH74-c3)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63) (0.188 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-c3) (0.038 g). HPLC-MS (ammonium acetate) [M+H]⁺=341.31.

(R,S)-1-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one(107LH74-c4)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63) (0.094 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-c4) (0.025 g). HPLC-MS (ammonium acetate)[M+H]⁺=369.33.

(R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-1H-quinolin-2-one(107LH74-c5)

Crude (R,S)-1-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one(107LH63) (0.094 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-c5) (0.023 g). HPLC-MS (ammonium acetate)[M+H]⁺=383.34.

(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH74-d1)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69) (0.165 g), 4-butylpiperidine (0.042 g, 0.30 mmol), NaI (0.100g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) were reactedand purified according to GP20 to give the title compound (107LH74-d1)(0.094 g). HPLC-MS (ammonium acetate) [M+H]⁺=375.31.

(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)-6-methoxy]-4H-benzo[1,4]oxazin-3-one(107LH74-d2)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69) (0.165 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-d2) (0.086 g). HPLC-MS (ammonium acetate) [M+H]⁺=377.29.

(R,S)-4-[3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH74-d3)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69) (0.165 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), NaI(0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF (1 mL) werereacted and purified according to GP20 to give the title compound(107LH74-d3) (0.086 g). HPLC-MS (ammonium acetate) [M+H]⁺=373.29.

(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH74-d4)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69) (0.082 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-d4) (0.044 g). HPLC-MS (ammonium acetate)[M+H]⁺=401.32.

(R,S)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH74-d5)

Crude(R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69) (0.082 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15mmol), NaI (0.100 g, 0.67 mmol), and K₂CO₃ (0.075 g, 0.54 mmol) in DMF(1 mL) were reacted and purified according to GP20 to give the titlecompound (107LH74-d5) (0.051 g). HPLC-MS (ammonium acetate)[M+H]⁺=415.34.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline(55-LH-12-2)

A solution of n-butyllithium in hexane (1.5M, 7.3 mL, 11 mmol) was addeddrop wise to a solution of 1,2,3,4-tetrahydro-quinoline (1.256 mL, 10mmol) in tetrahydrofuran (10 mL) at −78° C. under an atmosphere ofargon. The reaction mixture was stirred for ½ h then1-chloro-3-iodopropane (1.0 mL, 9.5 mmol) was added. The reactionmixture was stirred at −78° C. for ½ h then stirred for additional 16 hat room temperature. Tetrahydrofuran was evaporated off and the solidwas dissolved in acetonitrile (10 mL). KI (1.83 g, 11 mmol), K₂CO₃ (2.76g, 20 mmol) and 4-butylpiperidine (1.66 mL, 10 mmol) were added. Theslurry was stirred at 50° C. for 48 h then water (10 mL) was added andthe product was extracted with ethyl acetate (2×20 mL). The organiclayer was dried (Na₂SO₄) and concentrated in vacuo. The product waspurified by column chromatography (eluent: ethyl acetate) to give thetitle compound (1.11 g, 35%) Oxalate-salt was prepared from oxalic acid(1.1 eq.) in acetone. HPLC-MS: M+1⁺=315.1 (MS (%)=95). ¹H NMR (400 MHz,CDCl₃): δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.64-1.70 (2H, m), 1.79 (2H,quin.), 1.85-1.98 (4H, m), 2.36 (2H, t), 2.74 (2H, t), 2.92 (2H, broadd), 3.24-3.31 (4H, m), 6.54 (1H, ddd), 6.60 (1H, dd), 6.93 (1H, dd),7.03 (1H, ddd). ¹³C NMR (CDCl₃): d 14.3, 22.5, 23.1, 24.2, 28.4, 29.3,32.7, 36.0, 36.5, 49.6, 49.8, 54.4, 56.7, 110.9, 115.5, 122.5, 127.3,129.3, 145.6.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1,2,3,4-tetrahydro-quinoline(55-LH-28-8)

2-Methyl-1,2,3,4-tetrahydroquinoline (346 mg, 2.35 mmol) was convertedto the title product according to the procedure for the synthesis of1-[3-(4-butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline.Yield: 88.6 mg, 11%. HPLC-MS: M+1⁺=329.5 (UV/MS (%)=100/99). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.11 (3H, d), 1.16-1.34 (9H, m), 1.67 (2H,broad d), 1.65-2.03 (8H, m), 2.39 (2H, t), 2.57-2.66 (1H, m), 2.74-2.85(1H, m), 2.93 (2H, broad d), 3.12-3.21 (1H, m), 3.33-3.42 (1H, m),3.44-3.52 (1H, m), 6.45 (1H, t), 6.54 (1H, d), 6.87 (1H, d), 6.97 (1H,t).¹³C NMR (CD₃OD): d 13.2, 17.8, 22.8, 23.7 24.4, 28.0, 28.9, 31.9,35.7, 36.2, 52.7, 53.9, 54.0, 56.4, 110.8, 115.1, 121.9, 126.7, 128.7,144.2.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-1,2,3,4-tetrahydro-quinoline(55-LH-44A)

6-Methyl-1,2,3,4-tetrahydroquinoline (346 mg, 2.35 mmol) was convertedto the title product according to the procedure for the synthesis of1-[3-(4-butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline.Yield: 137 mg, 18%. HPLC-MS: M+1⁺=329.5 (UV/MS (%)=98/99). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.14-1.34 (9H, m), 1.68 (2H, broad d), 1.76(2H, quin.), 1.85-1.99 (4H, m), 2.14 (3H, s), 2.34-2.39 (2H, m), 2.66(2H, t), 2.92 (2H, broad d), 3.18-3.26 (4H, m), 6.49 (1H, d), 6.58 (1H,broad s), 6.76 (1H, broad d). ¹³C NMR (CD₃OD): d 13.2, 19.2, 22.5, 22.8,23.2, 28.0, 28.9, 31.9, 35.7, 36.2, 49.4, 49.6, 53.9, 56.5, 111.3,122.7, 124.7, 127.2, 129.6, 143.2.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline(77-LH-1)

8-Methyl-1,2,3,4-tetrahydroquinoline (125 mg, 0.85 mmol),1-chloro-3-iodopropane (82 μI, 0.77 mmol) and Cs₂CO₃ (415 mg, 1.27 mmol)in acetonitrile (2 mL) were shaken at 60° C. for 7 days. KI (140 mg,0.85 mmol), K₂CO₃ (117 mg, 0.85 mmol) and 4-butylpiperidine (113 μl,0.68 mmol) were added and the reaction mixture was shaken at 60° C. for2 days. Water (5 mL) was added and the product was extracted with ethylacetate (2×10 mL). The organic layer was dried (Na₂SO₄) and concentratedin vacuo. The product was purified by column chromatography (eluent: 20%methanol in ethyl acetate) to yield the title compound. Yield: 45.6 mg(20.4%). HPLC-MS: M+1⁺=329.5 (UV/MS (%)=99/97). ¹H NMR (400 MHz, CDCl₃):δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.70 (2H, broad d), 1.75-1.92 (4H,m), 1.99 (2H, broad t), 2.22 (3H, s), 2.38 (2H, dd), 2.70-2.81 (4H, m),2.96 (2H, broad d), 3.04-3.10 (2H, m), 6.76 (1H, t), 6.80 (1H, broad d),6.91 (1H, broad d). ¹³C NMR (CD₃OD): d 13.2, 17.2, 18.0, 18.1, 22.8,25.7, 27.7, 28.9, 31.9, 35.7, 36.2, 52.7, 53.9, 56.3, 121.5, 127.1,128.7, 128.9, 131.0, 148.0.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline(77-LH-2)

7-Fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline (165 mg, 1.0 mmol) wasconverted to the title product according to the procedure for thesynthesis of1-[3-(4-butyl-piperidin-1-yl)-propyl]-8-methyl-1,2,3,4-tetrahydro-quinoline.Yield: 43.2 mg, 16%. HPLC-MS: M+1⁺=347.5 (UV/MS (%)=95/92). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.10 (3H, d), 1.18-1.36 (9H, m), 1.66-1.91(6H, m), 2.00-2.10 (2H, m), 2.44 (2H, t), 2.62 (1H, dt), 2.74-2.85 (1H,m), 2.99 (2H, broad d), 3.16 (1H, q), 3.30-3.40 (1H, m), 3.41-3.49 (1H,m), 6.63-6.74 (1H, m), 6.63-6.74 (2H, m). ¹³C NMR (CD₃OD): d 13.2, 17.6,22.7, 23.7, 23.8, 24.3, 29.9, 28.9, 31.7, 35.5, 36.1, 52.6, 53.8, 56.2,112.7 (d), 114.8 (d), 123.7, 140.8, 153.5, 155.8.

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-trifluoromethyl-12.3.4-tetrahydro-quinoline(55-LH-54)

7-Trifluoromethyl-1,2,3,4-tetrahydro-quinoline (0.50 g, 2.5 mmol) wasconverted to the title product according to the procedure for thesynthesis of1-[3-(4-butyl-piperidin-1-yl)-propyl]-1,2,3,4-tetrahydro-quinoline.Yield: 1.71 mg, 18%. HPLC-MS: M+1⁺=347.5 (UV/MS (%)=99/91). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.14-1.36 (9H, m), 1.68 (2H, broad d), 1.79(2H, quin.), 1.86-2.03 (4H, m), 2.38 (2H, dd), 2.75 (2H, dd), 2.94 (2H,broad d), 3.32 (4H, m), 6.71 (1H, d), 6.75 (1H, s), 6.99 (1H, d).

1-[3-(4-Butyl-piperidin-1-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one(77-LH-28-1)

A suspension of NaH in mineral oil (55-60%) (712 mg) was added to asolution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) inN,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirredat 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) wasadded. The slurry was stirred for additional 16 h. at ambienttemperature then water (50 mL) was added and the product was extractedwith diethyl ether (2×50 mL). The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. The product was purified by flash-chromatography(eluent: dichloromethane) to give1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI(2.5 g, 15 mmol), K₂CO₃ (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL,15 mmol) were added to a solution of1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) inacetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16h. The acetonitrile was evaporated in vacuo, water (50 mL) was added andthe product was extracted with ethyl acetate (2×50 mL). The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by flash-chromatography (eluent: ethyl acetate) gave thetitle product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalicacid (1.1 eq.) in acetone. HPLC-MS: M+1⁺=329.5 (UV/MS (%)=100/100). ¹HNMR (400 MHz, CD₃OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broadd), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t),2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d),7.20 (1H, broad d), 7.25 (1H, broad t). ¹³C NMR (CD₃OD): d 13.2, 22.8,24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9,115,2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.51-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methoxy-3,4-dihydro-1H-quinolin-2-one(77-LH-22A)

6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg, 0.61 mmol),1-chloro-3-iodopropane (64 μl, 0.6 mmol) and Cs₂CO₃ (290 mg, 0.9 mmol)in acetonitrile (2 mL) were shaken at 60° C. for 14 h then the reactionwas cooled to room temperature. Water (5 mL) was added and the productwas extracted with ethyl acetate (2×10 mL). The organic layer was dried(Na₂SO₄), filtered and concentrated in vacuo. The syrup was dissolved inacetonitrile (4 mL). KI (83 mg, 3.6 mmol), K₂CO₃ (100 mg, 0.6 mmol) and4-butylpiperidine (83 μl, 0.5 mmol) were added and the reaction mixturewas shaken at 60° C. for 16 h. Water (5 mL) was added and the productwas extracted with ethyl acetate (2×10 mL). The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The product was purified by columnchromatography (eluent: 20% methanol in ethyl acetate) to yield thetitle compound. Yield: 24.8 mg, 11.3%. HPLC-MS: M+1⁺=359.5 (UV/MS(%)=90/78). ¹H NMR (400 MHz, CDCl₃): δ=0.89 (3H, t), 1.12-1.34 (9H, m),1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t),2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H,t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). ¹³C NMR (CDCl₃): d 14.3,23.0, 25.0, 26.1, 29.2, 32.1, 32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C),55.8, 56.3, 112.2, 114.2, 116.2, 128.3, 133.4, 155.4, 169.9

4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one64-(LHY-89-6)

6-Methyl-4H-benzo[1,4]oxazin-3-one (82 mg, 0.5 mmol),1-chloro-3-iodopropane (50 μl, 0.5 mmol) and Cs₂CO₃ (163 mg, 0.5 mmol)in acetonitrile (2 mL) were shaken at 50° C. for 24 h then the reactionmixture was concentrated in vacuo. The product(4-[3-chloropropyl]-6-methyl-4H-benzo[1,4]-oxazin-3-one) was purified onan Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethylacetate in heptanes) then dissolved in acetonitrile (2 mL). K₂CO₃ (85mg, 0.5 mmol) and 4-butylpiperidine (80 μl, 0.5 mmol) were added. Thereaction mixture was shaken at 60° C. for 16 h then cooled to roomtemperature. Dichloromethane (2 mL) and PS-isocyanate (loading 1.47mmol/g, 100 mg) were added. The mixture was filtered after 5 h and theorganic layer was loaded onto a Varian SCX ion exchange column. Thecolumn was washed with methanol (2×5 mL) then the product was eluted offthe column using 10% ammonium hydroxide in methanol (6 mL). The solutewas concentrated in vacuo to give the title product. Yield: 100 mg, 58%.HPLC-MS: M+1⁺=345.5 (UV/MS (%)=99/99). ¹H NMR (400 MHz, CDCl₃): δ=0.89(3H, t), 1.15-1.30 (9H, m), 1.65 (2H, broad d), 1.81-1.89 (4H, m), 2.30(3H, s), 2.36 (2H, t), 2.86 (2H, broad d), 3.94 (2H, dd), 4.51 (2H, s),6.76 (1H, dd), 6.84 (1H, d), 6.86 (1H, d). ¹³C NMR (CDCl₃): d 14.3,21.3, 23.1, 25.1, 29.2, 32.8 (2C), 36.0, 36.5, 39.8, 54.4 (2C), 56.1,67.9, 115.8, 116.9, 124.3, 128.6, 132.5, 143.4, 164.6.

6-Acetyl-4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(64-LHY-89-5)

6-Acetyl-4H-benzo[1,4]oxazin-3-one (96 mg, 0.5 mmol) was converted tothe title product according to the procedure for the synthesis of4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]-oxazin-3-one.Yield: 120 mg, 64%. HPLC-MS: M+1⁺=373.5 (UV/MS (%)=99/100). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.13-1.27 (9H, m), 1.63 (2H, broad d),1.81-1.88 (4H, m), 2.37 (2H, t), 2.55 (3H, s), 2.84 (2H, broad d), 4.02(2H, dd), 4.65 (2H, s), 6.99 (1H, d), 7.58 (1H, dd), 7.66 (1H, d).¹³CNMR (CDCl₃): d 14.3, 23.1, 24.7, 26.5, 29.2, 32.7 (2C), 36.0, 36.5,39.9, 54.4 (2C), 56.3, 67.6, 114.9, 117.0, 125.3, 128.8, 132.4, 149.5,163.5, 196.3.

4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine(64-LHY-91-6)

A solution of borane in THF (1M, 0.5 mL, 0.5 mmol) was added to asolution of4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(50 mg, 0.15 mmol) in THF (6 mL). The reaction mixture was stirred at40° C. for 16 h then aqueous HCl (4M, 10 mL) was added drop wise at roomtemperature. The reaction mixture was stirred for 16 h then concentratedin vacuo. A solution of K₂CO₃ (0.5 g) in water (5 mL) was added and theproduct was extracted with dichloromethane (2×10 mL). The organic layerwas dried (Na₂SO₄) and concentrated in vacuo. The product was purifiedon an Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethylacetate in heptanes+1% Et₃N). Yield: 29.2 mg, 56%. HPLC-MS: M+1⁺=373.5(UV/MS (%)=95/90). ¹H NMR (400 MHz, CDCl₃): δ=0.90 (3H, t), 1.18-1.35(9H, m), 1.68 (2H, broad d), 1.78 (2H, quin.), 1.89 (2H, broad t), 2.24(3H, s), 2.35 (2H, t), 2.89 (2H, broad d), 3.27 (2H, t), 3.31 (2H, t),4.19 (2H, t), 6.39 (1H, broad d), 6.52 (1H, broad s), 6.66 (1H, d). ¹³CNMR (CDCl₃): d 14.3, 21.4, 23.1, 24.2, 29.3, 32.8 (2C), 36.1, 36.6,47.4, 49.3, 54.5 (2C), 56.5, 64.7, 113.0, 116.2, 117.7, 131.1, 135.3,142.0.

4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[1,4]oxazine(64-LHY-91-5)

6-Acetyl-4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one(60 mg, 0.161 mmol) was converted to the title product according to theprocedure for the synthesis of4-[3-(4-butyl-piperidin-1-yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine.Yield: 22 mg, 40%. HPLC-MS: M+1⁺=373.5 (UV/MS (%)=98/97). ¹H NMR (400MHz, CDCl₃): δ=0.89 (3H, t), 1.18-1.35 (12H, m), 1.68 (2H, broad d),1.75 (2H, quin.), 1.89 (2H, broad t), 2.35 (2H, t), 2.53 (2H, qv), 2.89(2H, broad d), 3.26-3.33 (4H, m), 4.20 (2H, t), 6.43 (1H, dd), 6.53 (1H,d), 6.69 (1H, d). ¹³C NMR (CDCl₃): d 14.3, 16.2, 23.1, 24.2, 28.9, 29.3,32.8 (2C), 36.1, 36.6, 47.4, 49.4, 54.5 (2C), 56.5, 64.7, 112.0, 116.2,116.5, 135.3, 137.7, 142.2.

4-(3-Chloropropyl)-4H-benzo[1,4]thiazin-3-one (81MF07)

2H-1,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs₂CO₃ (2.96 g,9.08 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogenatmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.37 g,6.66 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. Thereaction mixture was stirred at rt for 18 hours and concentrated invacuo. Water (150 mL) was added and the reaction mixture was extractedwith ethyl acetate (3×150 mL). The combined organic phases were dried(MgSO₄) and concentrated in vacou to give 1.45 g of crude. The crudeproduct was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the puretitle compound as a slightly yellow oil. Yield 1.37 g, 90.2%. R_(f)=0.24[Heptane:EtOAC(4:1)], ¹H NMR (CDCl₃): d 2.14 (m, 2H), 3.38 (s, 2H), 3.36(t, 2H), 4.17 (t, 2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37(d, 1H). ¹³C NMR (CDCl₃): d 30.61, 31.81, 42.48, 42.66, 117.87, 123.78,124.29, 127.52, 127.52, 128.78, 139.40, 165.51

4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]thiazin-3-one(81MF09)

NaI (1.24 g, 8.27 mmol), K₂CO₃ (1.14 g, 8.27 mmol), and4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) werestirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]thiazin-3-one (1.0 g,4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reactionwas stirred at 60° C. for 13 hours and then at 80° C. for another 25hours under nitrogen atmosphere and concentrated in vacuo. Water (150mL) was added and the reaction mixture was extracted with ethyl acetate(3×150 mL). The combined organic phases were dried (Na₂SO₄) andconcentrated in vacuo to give 1.63 g of crude. The crude product wassubjected to CC[eluent:EtOAC:MeOH(100:1-5%) to give the pure titlecompound. Yield 1.06 g 74.2% HPLC-MS [M+H]⁺ 347 (UV/MS (%)=100/99. ¹HNMR (CDCl₃): d 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H),2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H),7.22 (d, 2H), 7.34 (d, 1H), ¹³C NMR (CDCl₃): d 14.21, 23.03, 25.23,29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45,124.17, 127.27, 128.56, 139.63, 165.19.

To 4-[3-(4-butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]thiazin-3-one(1.06 g, mmol) in 30 ml diethyl ether was charged oxalic acid (0.28 g,3.1 mmol) dissolved in diethyl ether (5 mL). The formed crystals werefiltered of and washed with diethyl ethyl (5×10 mL) to give 1.21 g ofthe oxalic salt after drying. HPLC-MS [M+H]⁺ 347 (UV/MS (%)=100/99

4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one (81MF08)

2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs₂CO₃ (3.28 g, 10.1mmol) were dissolved in dry acetonitrile (20 mL) under nitrogenatmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g,7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. Thereaction mixture was stirred at rt for 18 hours and concentrated invacuo. Water (150 mL) was added and the reaction mixture was extractedwith ethyl acetate (3×150 mL). The combined organic phases were dried(MgSO₄) and concentrated in vacou to give 1.65 g of crude. The crudeproduct was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the puretitle compound as a colorless oil. Yield 1.36 g, 89.2%. R_(f)=0.24[Heptane:EtOAC(4:1)], ¹H NMR (CDCl₃): d 2.16 (m, 2H), 3.62 (t, 2H), 4.10(t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), ¹³C NMR (CDCl₃): d30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49,145.47, 164.58.

4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one (81MF10)

NaI (1.33 g, 8.87 mmol), K₂CO₃ (1.23 g, 8.90 mmol), and4-(3-butylpiperidine (0.66 g, 4.71 mmol) in acetonitrile (10 mL) werestirred at rt. 4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 g, 4.43mmol) in acetonitrile (15 mL) was added via a syringe. The reaction wasstirred at 60° C. for 13 hours and then at 80° C. for another 5 hoursunder nitrogen atmosphere and concentrated in vacuo. Water (150 mL) wasadded and the reaction mixture was extracted with ethyl acetate (3×150mL). The combined organic phases were dried (Na₂SO₄) and concentrated invacuo to give 1.58 g of crude. The crude product was subjected toCC[eluent:EtOAC:MeOH(100:1-5%)] to give the pure title compound. Yield0.82 g 56.0% HPLC-MS [M+H]⁺331 (UV/MS (%)=100/99. ¹H NMR (CDCl₃): d 0.88(t, 3H), 1.21 (m, 6H), 1.26 (m, 3H), 1.66 (d, 2H), 1.86 (m, 4H), 2.37(t, 2H), 2.86, (d, 2H), 3.97 (t, 2H), 4.58 (s, 2H), 6.99 (m, 3H), 7.11(d, 1H), ¹³C NMR (CDCl₃): d 14.22, 23.04, 24.90, 29.17, 32.68, 35.95,36.46, 39.74, 54.31, 56.02, 67.77, 115.26, 117.15, 122.83, 123.83,128.78, 145.50, 164.34.

To 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-4H-benzo[1,4]oxazin-3-one (0.82g, mmol) in 30 ml diethyl ether was charged oxalic acid (0.25 g, 2.8mmol) dissolved in diethyl ether (5 mL). The formed crystals werefiltered of and washed with diethyl ether (5×10 mL) to give 0.75 g ofthe oxalic salt after drying. HPLC-MS [M+H]⁺ 331 (UV/MS (%)=100/99

EXAMPLE 1 Additional Synthetic Chemistry General Analytical LC-MSProcedure Procedure 1:

Spectra were obtained using a HP 1100 LC/MSD-instrument. A set-up with abinary pump, auto sampler, column oven, diode array detector, andelectro spray ionisation interface was used. A reversed phase column(C18 Luna 3μ, 75×4.6 mm ID) with a guard column cartridge system wasused. The mobile phase was MeCN/8 mM aqueous ammonium acetate. A15-minute gradient program was used, starting at 70% MeCN over 12minutes to 95% MeCN, over 1 minute to 70% MeCN, hold for 2 minutes. Theflow rate was 0.6 ml/min.

Procedure 2:

Spectra were obtained using a Waters LC/ZMD-instrument. A set-up with a600 gradient pump, 2700 sample manager, 996 diode array detector, andelectro spray ionisation interface was used. A reversed phase column(C18 X-Terra 5μ, 50×4.6 mm ID) with a guard column cartridge system wasused. The mobile phase was MeCN/10 mM aqueous ammonium acetate. A14-minute gradient program was used; starting at 30% MeCN, over 10minutes to 95% MeCN, hold for 2 minutes, over 0.5 minutes to 30% MeCN,hold for 4.5 minutes. The flow rate was 1 ml/min.

General Preparative LC-MS Procedure

Preparative purification was performed on Waters Delta 4000 preparativesystem, Water 2487 dual absorbance detector, and Waters Fractioncollector II. The column used was a Luna 15 μm C18, 250×21.2 mm. Thefollowing mobile phases were used: H₂O/MeCN ammonium acetate buffer (25nM) or H₂O/MeCN TFA buffer (25 nM).

Cation exchange column chromatography was performed with Varian BONDELUT (mega BE-SCX, 1 g, 6 ml) columns. After applying the compound tothe column, it was first washed with MeOH (2 column volumes) andthereafter the desired compound was eluted applying 2 column volumes ofan NH₄OH (25% NH₃ in H₂O)/MeOH mixture (1:9).

General Procedure 1 (GP1)

A flask or vial was charged with 2-aminophenol (1.0 equiv) dissolved inDMF (0.1 g/ml) and 2-chloroacetyl chloride (1.1 equiv) was added. Thereaction was stirred at r.t. for 12-20 hours and K₂CO₃ (2.1 equiv) wasadded. The reaction was stirred at r.t. for another 12-20 hours thenevaporated to dryness. The reaction mixture was redisolved redisolved inwater (100 ml) and extracted using EtOAc (3×150 ml). The combinedorganic phases were dried over Na₂SO₄ and concentrated to a crude thatwas used directly or purified by column chromatography (heptanes/EtOAc)or (CH₂Cl₂/MeOH).

5,7-Difluoro-4H-benzo[1,4]oxazin-3-one

2-Amino-3,5-diflourophenol (1.85 g, 12.7 mmol), 2-chloroacetyl chloride(1.58 g, 14 mmol) and K₂CO₃ (3.69 g, 26.7 mmol) were mixed according toGP1. Purified by column chromatography (SiO₂; heptanes/EtOAc 4:1) togive the title compound (111MF84) (0.49 g, 21%). R_(f)=0.21(heptanes:EtOAc 4:1); ¹H NMR (CDCl₃) d 8.32 (s, 1H), 6.66-6.51 (m, 2H),4.62 (s, 2H).

5,6-Difluoro-4H-benzo[1,4]oxazin-3-one

A crude of 2-amino-3,4-diflourophenol (0.68 g, 4.7 mmol), 2-chloroacetylchloride (0.58 g, 5.2 mmol) and K₂CO₃ (1.36 g, 9.9 mmol) were mixedaccording to GP1. Purified by prep RP-HPLC to give the title compound(0.127 g, 14.5%). R_(f)=0.63 (heptanes/EtOAc 1:1). ¹H NMR (CDCl₃) d6.69-6.57 (m, 2H), 4.47 (s, 2H); ¹³C NMR (CDCl₃) d 165.0, 146.2 (dd,J=241.8 Hz, J=10.4 Hz), 140.3 (t, J=2.32 Hz), 138.7 (dd, J=247.2 Hz,J=17.3 Hz), 67.1 (t, J=2.7 Hz).

6,7-Difluoro-4H-benzo[1,4]oxazin-3-one

A crude of 2-amino-4,5-diflourophenol (2.67 g, 18.4 mmol),2-chloroacetyl chloride (2.28 g, 20 mmol) and K₂CO₃ (5.34 g, 38.6 mmol)were mixed according to GP1. Purified by column chromatography (SiO₂;heptanes/EtOAc 4:1 to 1:1) to give the title compound (2.17 g, 64%).R_(f)=0.43 (heptanes/EtOAc 1:1); Mp=214.5-219.2° C.; ¹H NMR (CD₃OD) d6.90 (dd, J=11.4 Hz, J=7.2 Hz, 1H), 6.80 (dd, J=11.0 Hz, J=7.7 Hz, 1H),4.56 (s, 2H); ¹³C NMR (CD₃OD) d 167.0, 147.0 (dd, J=243.5 Hz, J=13.8Hz), 146.9 (dd, J=240.0 Hz, J=13.8 Hz), 141.2 (dd, J=9.8 Hz, J=3.0 Hz),124.8 (dd, J=8.7 Hz, J=3.0 Hz), 106.9 (dd, J=22.0 Hz, J=6.9 Hz), 105.5(dd, J=23.1 Hz, J=4.6 Hz), 68.1 (t, J=6.5 Hz).

6.8-Difluoro-4H-benzo[1,4]oxazin-3-one

2-Amino-4,6-diflourophenol (1.98 g, 13.6 mmol), 2-chloroacetyl chloride(1.69 g, 15 mmol) and K₂CO₃ (3.95 g, 28.5 mmol) were mixed according toGP1. Purified by column chromatography (SiO₂; CH₂Cl₂/MeOH 99:1) to givethe title compound (149MF24) (1.5 g, 59%). R_(f)=0.50 (heptanes/EtOAc1:1); ¹H NMR (DMSO) d 6.92-6.86 (m, 1H), 6.59-6.54 (m, 1H), 4.62 (s,2H); ¹³C NMR (DMSO) d 165.0, 156.4 (dd, J=239.0 Hz, J=13.1 Hz), 150.5(dd, J=267.3 Hz, J=14.6 Hz), 130.1 (dd, J=13.4 Hz, J=5.8 Hz), 128.3 (dd,J=14.6 Hz, J=3.8 Hz), 98.8 (dd, J=26.9 Hz, J=3.5 Hz), 98.5 (dd, J=27.6Hz, J=22.6 Hz), 67.0.

5,8-Difluoro-4H-benzo[1,4]oxazin-3-one

2-Amino-3,6-diflourophenol (0.44 g, 3.0 mmol), 2-chloroacetyl chloride(0.38 g, 3.3 mmol) and K₂CO₃ (0.88 g, 6.4 mmol) were mixed according toGP1. Purified by extraction gave the title compound (0.52 g, 93%).R_(f)=0.57 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d 8.02 (s, 1H),7.78-6.69 (m, 2H), 4.72 (s, 2H); ¹³C NMR (CDCl₃) d 163.7, 148.0 (dd,J=242.4 Hz, J=2.1 Hz), 145.9 (d, J=237.9 Hz), 132.9 (dd, J=16.7 Hz,J=4.4 Hz), 117.2 (dd, J=16.9 Hz, J=3.8 Hz), 110.2 (dd, J=20.5 Hz, J=8.6Hz), 108.6 (dd, J=20.0 Hz, J=7.7 Hz), 67.4.

8-Ethyl-4H-benzo[1,4]oxazin-3-one

6-Ethyl-2-aminophenol (0.88 g, 6.4 mmol), 2-chloroacetyl chloride (0.80g, 7.0 mmol) and K₂CO₃ (1.86 g, 13.5 mmol) were mixed according to GP1.Purified by column chromatography (SiO₂; CH₂Cl₂/MeOH 99:1) to give thetitle compound (0.69 g, 61%). R_(f)=0.54 (heptanes/EtOAc 1:1); ¹H NMR(CDCI₃) d 9.29 (s, 1H), 6.92-6.85 (m, 2H), 6.71 (dd, J=7.0 Hz, J=2.6Hz), 4.62 (s, 2H), 2.65 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); ¹³CNMR (CDCl₃) d 166.8, 141.6, 133.0, 126.1, 124.4, 122.5, 114.0, 67.3,22.9, 14.4.

4-Cyclopropylmethoxypiperidine-1-carboxylic acid t-butyl ester

A reaction flask was charged with 4-hydroxypiperidine-1-carboxylic acidt-butyl ester (10.05 g, 49.9 mmol) in dry DMF (50 mL) under Argon. NaH(60% in oil, 2.0 g, 50.0 mmol) was added in portions and the mixture wasstirred at 50° for 1 h. The mixture was cooled to rt andbromomethylcyclopropane (6.752 g, 50.0 mmol) was added followed bystirring at rt for 20 h under Argon. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organicphases were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash column chromatography (SiO₂; n-heptane/EtOAc 2:1)to give the title compound (6.809 g, 53%). ¹H NMR (CDCl₃) d 3.66-3.58(m, 2H), 3.31-3.24 (m, 1H), 3.12 (d, 2H), 2.90-2.83 (m, 2H), 1.68-1.60(m, 2), 1.38-1.30 (m, 2H), 1.28 (s, 9H), 0.91-0.82 (m, 1H), 0.38-0.33(m, 2H), 0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 154.8, 79.3, 74.4, 72.6,41.4, 31.2, 28.4, 10.9, 3.0

4-Cyclopropylmethoxypiperidine

A reaction flask was charged with4-cyclopropylmethoxypiperidine-1-carboxylic acid t-butyl ester (6.80 g,26.6 mmol) in DCM (15 mL). TFA (7 mL) was added and the reaction wasstirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOHand the product extracted into diethyl ether. The combined organicphases were dried over Na₂SO₄, filtered, and concentrated to give thetitle compound (3.949 g, 95%). ¹H NMR (CD₃CD) d 3.34-3.24 (m, 1H), 3.15(d, 2H), 2.88-2.82 (m, 2H), 2.44-2.37 (m, 2H), 1.78-1.70 (m, 2H),1.31-1.21 (m, 2H), 0.89-0.79 (m, 1H), 0.37-0.32 (m, 2H), 0.04-0.00 (m,2H); ¹³C NMR (CD₃OD) d 76.2, 73.6, 44.7, 33.2, 11.7, 3.5.

4-Cyclobutylmethoxypiperidine-1-carboxylic acid t-butyl ester and4-cyclobutylmethoxycarbonyloxypiperidine-1-carboxylic acid t-butyl ester

A reaction flask was charged with 4-hydroxypiperidine-1-carboxylic acidt-butyl ester (1.00 g, 4.97 mmol) in dry DMF (5 mL) under Argon. NaH(60% in oil, 0.298 g, 7.5 mmol) was added in portions and the mixturewas stirred at rt for 1 h under Argon. Then bromomethylcyclopropane(1.118 g, 7.5 mmol) was added followed by stirring at rt for 20 h underArgon.

A reaction flask was charged with 4-hydroxypiperidine-1-carboxylic acidt-butyl ester (0.201 g, 1.0 mmol) and Cs₂CO₃ (0.342 g, 1.05 mmol) in DMF(1 mL) and stirred at 95° for 1 h. bromomethylcyclobutane (0.149 g, 1.0mmol) was then added and the reaction was stirred at 95° for another 20h.

The two reaction mixtures were quenched with water and the productsextracted into EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The reaction mixture was purified byflash column chromatography (SiO₂; n-heptane/EtOAc 1:1) to give amixture of the two title compounds (0.190 g).

4-Cyclobutylmethoxypiperidine and carbonic acid cyclobutylmethyl esterpiperidine-4-yl ester

A reaction flask was charged with a mixture of4-cyclobutylmethoxypiperidine-1-carboxylic acid t-butyl ester and4-cyclobutylmethoxycarbonyloxypiperidine-1-carboxylic acid t-butyl ester(0.189 g) in DCM (2 mL). TFA (1 mL) was added and the reaction wasstirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOHand the products extracted into diethyl ether. The combined organicphases were dried over Na₂SO₄, filtered, and concentrated to give amixture of the two title compounds (0.100 g)

2,2-Dimethylpropionic acid piperidin-4-ylmethyl ester

To 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butylester (480 mg,2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol,55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. Themixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml,1.3 mmol) was added. The reaction was allowed to stir over night andthen poured into water and the mixture was extracted with ether. Thecombined organic phases were washed with brine, dried (Na₂SO₄),filtered, concentrated under reduced pressure and the oily residue waspurified by Flash column chromatography (SiO₂; heptane/EtOAc 70:30) toyield 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acidt-butyl ester as an oil. Deprotection of4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butylester was conducted using the method (CH₂Cl₂:TFA; 1:1) to yield thetitle compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was usedwithout further purification.

2,2-Dimethylpropionic acid 2-piperidin-4-yl-ethyl ester

To 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (480mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2h. The mixture was allowed to cool to rt and then pivaloyl chloride(0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir overnight and then poured into water and the mixture was extracted withether. The combined organic phases were washed with brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The oilyresidue was purified by Flash column chromatography (SiO₂; heptane/EtOAc70:30) to yield4-[2-(2,2-dimethylpropionyloxy)ethyl]-piperidine-1-carboxylic acidtert-butyl ester as an oil, which was deprotected in CH₂Cl₂/TFA,employing the standard procedure. This yielded the crude title compoundas an oil (94 mg, 0.44 mmol, 34%), which was used without furtherpurification.

3a-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester

A reaction flask was charged with 8-azabicyclo[3.2.1]octan-3a-ol (42.3g, 0.33 mol) and di-t-butyldicarbonate (80 g, 0.37 mol) in MeCN (500 mL)and 1 M NaOH (150 mL). The reaction was stirred at rt for 20 h. Thenwater was added and the product extracted into EtOAc. The combinedorganic phases were washed with 5% aqueous citric acid and brine, thendried over Na₂SO₄, filtered, and concentrated. The solid material waswashed with n-heptane and dried to give the crude title compound (76.19g).

3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester

A reaction flask was charged with crude3a-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester(5.5 g) in dry DMF (25 mL) under Argon. NaH (60% in oil, 0.968 g, 24.2mmol) was added in portions and the mixture was stirred at 50° for 1 h.The mixture was cooled to rt and bromomethylcyclopropane (3.252 g, 24.2mmol) was added followed by stirring at rt for 20 h under Argon. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂; n-heptane/EtOAc 2:1) to give the title compound (3.354 g). ¹H NMR(CDCl₃) d 3.98-3.94 (m, 2H), 3.44-3.40 (m, 1H), 3.05 (d, 2H), 1.96-1.88(m, 2H), 1.79-1.62 (m, 6H), 1.29 (s, 9H), 0.88-0.79 (m, 1H), 0.35-0.30(m, 2H), 0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 153.4, 78.9, 73.0, 72.5,52.7, 34.9, 28.5, 28.1, 10.9, 2.8.

3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]octane

A reaction flask was charged with3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (3.35 g, 11.9 mmol) in DCM (5 mL). TFA (5 mL) was addedand the reaction was stirred at rt for 4 h. The reaction mixture wasquenched with 1 M NaOH and the product extracted into EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated to give the title compound (2.028 g, 94%). ¹H NMR (CDCl₃) d3.38-3.37 (m, 1H), 3.33-3.28 (m, 2), 3.02 (d, J=6.5 Hz, 2H), 2.62 (br s,2H), 1.97-1.86 (m, 2H), 1.72-1.44 (m, 4H), 0.89-0.76 (m, 1H), 0.36-0.23(m, 2H), 0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 72.6, 72.2, 53.5, 36.5,29.0, 10.7, 2.6.

3-Ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester

A reaction flask was charged with triethyl phosphonoacetate (7.458 g,33.3 mmol) in dry THF (20 mL) under Argon. NaH (60% in oil, 1.33 g, 33.3mmol) was added in portions and the mixture was stirred at rt for 1 h.The clear solution was cooled to <10° with an icebath followed bydropwise addition of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (4.977 g, 22.2 mmol) dissolved in THF (5 mL) over 45 min.The temperature was slowly raised to rt. The reaction was stirred for 20h. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flashcolumn chromatography (SiO₂; n-heptane/EtOAc 4:1) to give the titlecompound (5.416 g, 82%). ¹H NMR (CDCl₃) d 5.76-5.74 (m, 1H), 4.28 (br s,2H), 4.19-4.07 (m 2), 3.66-3.59 (m, 1H), 2.76-2.20 (m, 2H), 2.11-2.06(m, 1H), 1.93-1.87 (m, 2H), 1.58-1.54 (m, 2H), 1.46 (m, 9H), 1.26 (t,3H).

3-(2-Hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester

A reaction flask was charged with3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (2.70 g, 9.1 mmol) in dry THF (15 mL) under Argon. Thesolution was cooled to −78° and DIBAL-H (1.5 M in toluene, 13.7 mL, 20.5mmol) was added dropwise over 20 min. The reaction was stirred at −78°for 1 h then the temperature was raised to rt. The reaction mixture wasadded i-propanol (5 mL) and stirred at rt for 5 min followed by additionof water (10 mL). DCM was added and the suspension was stirred at rt for15 min. The suspension was filtered and the collected organic phase wasdried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash column chromatography (SiO₂; n-heptane/EtOAc 1:1; EtOAc) togive the title compound (1.908 g, 82%). ¹H NMR (CDCl₃) d 5.57-5.51 (m,1H), 4.24-4.17 (m, 2H), 4.36-4.06 (m, 2H), 2.54-2.46 (m, 1H), 2.40-2.34(m, 1H), 2.24-2.18 (m, 1H), 2.01-1.96 (m, 1H), 1.90-1.78 (m, 3H),1.60-1.46 (m, 2H), 1.45 (s, 9H).

3-(2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid t-butyl ester

A reaction flask was charged with3-(2-hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (0.380 g, 1.5 mmol) in dry DMF (2 mL) under Argon. NaH(60% in oil, 0.060 g, 1.5 mmol) was added in portions and the mixturewas stirred at 50° for 1 h. The mixture was cooled to rt andbromomethylcyclopropane (0.202 g, 1.5 mmol) was added followed bystirring at rt for 20 h under Argon. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organicphases were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash column chromatography (SiO₂; n-heptane/EtOAc 1:1)to give the title compound (0.115 g, 25%). ¹H NMR (CDCl₃) d 5.38-5.32(m, 1H), 4.36-3.96 (m, 2H), 3.88-3.75 (m, 2H), 3.09 (d, 2H), 2.48-1.66(m, 6H), 1.48-1.36 (m, 2H), 1.30 (s, 9H), 0.94-0.33 (m, 1H), 0.40-0.33(m, 2H), 0.05-0.00 (m, 2)

3-(2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1)octane

A reaction flask was charged with3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylicacid t-butyl ester (138LH49) (0.115 g, 0.37 mmol) in DCM (2 mL). TFA(0.5 mL) was added and the reaction was stirred at rt for 3 h. Thereaction mixture was quenched with 1 M NaOH and the product extractedinto diethyl ether. The combined organic phases were dried over Na₂SO₄,filtered, and concentrated to give the crude title compound (0.090 g).

3β-Butyl-3a-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

Dry CeCl₃ (2.5 g, 10 mmol) was ground to a fine powder and wasthereafter dried for 6 h at 100° C. under vacuum (>1 mm Hg). The powderwas then cooled on an ice bath under an Ar atmosphere, then cold and dryTHF (40 ml) was poured onto the white powder and was allowed to stir at0° C. for 15 min and the stirring was then continued at rt overnight.The resulting thick slurry was cooled to −78° C., and n-BuLi (7.1 ml,1.4 M) was added. After stirring for 1 h at −78° C. the mixture hadbecome slightly greenish and then3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(0.56 g, 2.5 mmol) dissolved in THF (10 ml) was slowly added. Thereaction was allowed to reach rt overnight, quenched with sat aq NaCl(10 ml), the phases were separated and the water phase was extractedwith EtOAc. The combined organic phases were washed with brine, dried(Na₂SO₄), filtered, concentrated under reduced pressure and the oilyresidue was purified by flach column chromatography (SiO₂;heptane/EtOAC,90:10 to 25:75) to yield the title compound as a clear, colorless oil(0.48 g, 17 mmol, 68%). ¹³C NMR (CDCl₃) d 153.8, 79.2, 71.6, 53.5 (vbr),52.8 (vbr), 46.9, 42.9 (vbr), 42.3 (vbr), 28.7, 28.2 (vbr), 27.7 (vbr),25.1, 23.3, 14.2; HPLC-MS (ammonium acetate) [M+H]⁺=228.20.

3-β-Butyl-8-aza-bicyclo[3.2.1]octan-3a-ol

Deprotection of3R-butyl-3a-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (0.10 g, 0.35 mmol) was conducted using the method(CH₂Cl₂:TFA; 1:1) to yield the title compound as an oil (40 mg, 0.22mmol, 62%). HPLC-MS (ammonium acetate) [M+H]⁺=184.19.

(8-Azabicyclo[3.2.1]oct-3-ylidene)acetic acid ethyl ester

To 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (12.3 g, 41.8 mmol) in CH₂Cl₂ was added TFA (10 ml) andthe reaction was stirred for 8 h. The solution was concentrated underreduced pressure, diluted with CH₂Cl₂, and washed first with 2 M NaOHand followed by brine. The water phases were thereafter back-extractedwith EtOAc and the combined organic phase was dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The crude title product wasused without further purification (7.04 g, 37.9 mmol, 91%).

(8-Azabicyclo[3.2.1]oct-3a-yl)acetic acid ethyl ester

A 250 ml reaction flask was charged with(8-azabicyclo[3.2.1]oct-3-ylidene)acetic acid ethyl ester (3.7 g, 19mmol), ammonium formiate (14 g, 190 mmol), and Pd/C (0.32 g, 8.6%) in150 ml MeOH. When all of the ammonium formiate was dissolved a slightunder pressure was applied on the mixture for 15 min. The reaction wasstirred on under an inert atmosphere (N₂) over night at rt. The reactionwas filtered through celite, concentrated under reduced pressure,diluted with 2 M NaOH (ca pH 10), and extracted with EtOAc. The combinedorganic phases were washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The crude title product (3.1 g, 16mmol, 83%; 85:15 a:β) that was used without further purification. Majorisomer: ¹H NMR (CDCl₃) d 4.08 (q, J=7.2 Hz, 2H), 3.45-3.41 (m, 2H), 2.40(d, J=8.0 Hz, 2H), 2.25-2.18 (m, 1H), 2.06-1.96 (m, 2H), 1.82-1.55 (m,5H), 1.31-1.23 (m, 2H), 1.21 (t, J=7.2 Hz, 3 H); ¹³C NMR (CDCl₃) d173.3, 60.4, 53.6, 42.6, 36.7, 30.425.4, 14.4.

3a-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

A solution of BOC-anhydride (4.3 g, 20 mmol) in THF (10 ml) was added toa cooled solution of (8-azabicyclo[3.2.1]oct-3a-yl)acetic acid ethylester (2.8 g, 14 mmol) in THF (40 ml). The reaction was stirred at rtfor 14 h and concentrated under reduced pressure. The semi-solid residuewas diluted with EtOAc, washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The oily residue was purified byflash column chromatography (SiO₂; heptane/EtOAc 70:30) to yield thetitle compound as an oil (3.8 g, 11 mmol, 73%). Major isomer: ¹H NMR(CDCl₃) d 4.16 (vbr s, 2H), 4.11 (q, J=6.8 Hz, 2H), 2.43 (d, J=7.6 Hz,2H), 2.24-2.12 (m, 3H), 2.00-1.92 (m, 2H), 1.70-1.61 (M, 2H), 1.44 (s,9H), 1.23 (t, J=6.8 Hz, 3H).

3a-(2-Hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

Under an inert atmosphere a solution of DIBAL-H (20 ml, 1.5 M) intoluene was slowly added to a −72° C. solution of3a-ethoxycarbonylmethyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (3.7 g, 12 mmol) in dry THF (20 ml). The reaction wasallowed to stir at −72° C. for 1 h and was then allowed to slowly risein temperature. At −10° C. the reaction was quenched with i-PrOH,stirred for 15 min and the water was added. The resulting gel-likesubstance was filtered through celite with CH₂Cl₂ and the eluent waswashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The oily residue was purified by flash columnchromatography (SiO₂; heptane/EtOAc 40:60) to yield the title compoundas an oil (2.4 g, 9.4 mmol, 74%). Major isomer: ¹H NMR (CDCl₃) d 4.15(vbr s, 2H), 3.64 (t, J=4.4 Hz, 2H), 2.24-2.15 (m, 2H), 1.99-1,92 (m,2H), 1.77-1.61 (m, 5H), 1.44 (s, 9H), 1.28-1.17 (m, 2H); ¹³C NMR (CDCl₃)d 154.2, 79.2, 61.7, 52.4, 40.5, 35.9, 29.9, 28.7, 25.2.

3a-(2-Methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a solution of Et₃N (5 ml) in CH₂Cl₂ (20 ml)3a-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (2.3 g, 9.0 mmol) was dissolved and then cooled on anice bath. Thereafter, neat MsCl (1.0 ml, 13.5 mmol) was slowly added.The reaction was stirred at 0° C. for 5 min and then at rt for 2 h. Thereaction was quenched with brine, the phases were separated, and thewater phase was extracted with CH₂Cl₂. The combined organic phases werewashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The oily residue was purified by flash columnchromatography (SiO₂; heptane/EtOAc 50:50) to yield the title compoundas an oil (2.9 g, 8.6 mmol, 95%), which solidified upon standing.

3a-(2-Methoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

To a solution of3a-(2-methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (1.0 g, 3.0 mmol) in dry MeOH (7 mL) was added toa solution of NaOMe (17 mL, 2.8 M in MeOH). The reaction was stirredunder an inert atmosphere (N₂) at 40° C. for 6 days, concentrated,poured into brine, and extracted with ethyl acetate. The combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated. The oily residue was purified by flash columnchromatography (SiO₂; heptane/ethyl acetate 7:3) to yield the titlecompound (0.7 g, 86%) as an oil. Major isomer: ¹H NMR (CDCl₃) d 4.14(vbr s, 2H), 3.35 (t, J=6.4 Hz, 2H), 3.28 (s, 3 H), 2.16 (brs, 2H),1.98-1.87 (m, 2H), 1.74-1.62 (m, 5H), 1.44 (s, 9H), 1.25-1.15 (m, 2H),¹³C NMR (CDCl₃) d 154.1, 79.1, 71.8, 58.8, 52.6 (br), 37.4, 35.8 (br),29.8 (br), 28.7, 25.7.

3a-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester

A solution of3a-(2-methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (2.8 g, 8.4 mmol) in dry EtOH (15 ml) was added toa solution of NaOEt (17 ml, 2.8 M in EtOH). The reaction was stirredunder an inert atmosphere at 40° C. for 64 h, concentrated under reducedpressure, poured onto brine and extracted with EtOAc. The organic phasewas dried (Na₂SO₄), filtered, and concentrated under reduced pressure.The oily residue was purified by flash column chromatography (SiO₂;heptane/EtOAc 70:30) to yield the title compound as an oil (2.9 g, 7.1mmol, 83%). Major isomer: ¹H NMR (CDCl₃) d 4.14 (vbr s, 2H), 3.44 (t,J=7.2 Hz, 2H), 3.39 (q, J=6.6 Hz, 2H), 2.13 (m, 2H), 1.98-1.90 (m, 2H),1.74-1.62 (m, 5H), 1.44 (s, 9 H), 1.25-1.18 (m, 2H), 1.17 (t, J,=6.6Hz); ¹³C NMR (CDCl₃) d 154.1, 79.1, 69.6, 66.4, 52.5, 37.6, 35.9, 29.8,28.7, 25.7, 15.4.

3a-(2-Methoxyethyl)-8-azabicyclo[3.2.1]octane

To 3a-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (0.7 g, 2.6 mmol) in CH₂Cl₂ (2 ml) was added TFA (1 ml)and the reaction was stirred for 3 h. The solution was concentratedunder reduced pressure, diluted with diethyl ether, and the solution waswashed with aq NaOH (2M) and brine. The organic solution was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudetitle product (0.400 g, 91%) was used without further purification.

3a-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]octane

To 3a-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (2.0 g, 7.1 mmol) in CH₂Cl₂ (5 ml) was added TFA (5 ml)and the reaction was stirred for 4 h. The solution was concentratedunder reduced pressure, diluted with EtOAc, and the solution was washedwith aq NaOH (2M) and brine. The organic solution was dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The crude titleproduct (1.2 g, 6.3 mmol, 88%) was used without further purification.Major isomer: ¹H NMR (CDCl₃) d 3.47-3.34 (m, 6H), 2.04-1.94 (m, 2H),1.82-1.64 (m, 8H), 1.30-1.23 (m, 2H), 1.16 (t, J=7.2 Hz, 3H); ¹³C NMR(CDCl₃) d 69.8, 66.3, 53.7, 37.9, 37.3, 30.6, 25.3, 15.4

3β-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester

A reaction flask was charged with3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (0.260 g, 0.88 mmol) and Pd/C (0.026 g) in MeOH (4 mL).The reaction flask was evacuated and purged with hydrogen twice followedby stirring under a hydrogen atmosphere for 20 h. The reaction mixturewas filtered through Celite, washed with MeOH, and concentrated to givethe crude title compound as the major isomer (0.255 g, 97%; 1:3 a:β).Major isomer: ¹H NMR (CDCl₃) d 4.17-4.15 (m, 2H), 4.13-4.06 (m, 2H),2.32-2.26 (m, 1H), 2.13 (d, J=7.0 Hz, 2H), 1.95-1.90 (m, 2H), 1.67-1.61(m, 2H), 1.59-1.54 (m, 2H), 1.43 (s, 9H), 1.42-1.27 (m, 2), 1.22 (t,J=7.2 Hz, 3H); ¹³C NMR (CDCl₃) d 172.4, 153.3, 79.0, 60.2, 53.3, 41.3,37.2, 28.4, 26.0, 14.2

3β-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester

A reaction flask was charged with3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (0.254 g, 0.86 mmol) and PtO₂ (0.028 g) in MeOH (4 mL).The reaction flask was evacuated and purged with hydrogen twice followedby stirring under a hydrogen atmosphere for 20 h. The reaction mixturewas filtered through Celite, washed with MeOH, and concentrated to givethe crude title compound as the major isomer (0.256 g, 100%, 1:3 a:β).

3β-(2-Hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butylester

A reaction flask was charged with3β-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acidt-butyl ester (0.497 g, 1.67 mmol) in dry THF (2 mL) and the solutionwas cooled to −78°. DIBAL-H (1.5 M in toluene, 2.2 mL, 3.34 mmol) wasadded dropwise and the reaction was stirred at −78° for 1 h. Thetemperature was raised to rt, the reaction quenched with water, and theproduct extracted into DCM. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flashcolumn chromatography (SiO₂; n-heptane/EtOAc 1:1) to give the titlecompound (0.242 g, 57%).

3β-(2-Methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylicacid t-butyl ester

A reaction flask was charged with3β-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butylester (0.154 g, 0.61 mmol), methanesulfonyl chloride (0.105 g, 0.92mmol), and TEA (1 mL) in dry DCM (6 mL) and stirred at rt. After 30 min,more methanesulfonyl chloride (0.052, 0.45 mmol) was added and thereaction was stirred at rt for another 30 min. The reaction mixture wasquenched with water and the product extracted into DCM. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Theproduct was purified by flash column chromatography (SiO₂;n-heptane/EtOAc 2:1) to give the title compound (0.179 g, 89%).

3β-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butylester

A reaction flask was charged with3β-(2-methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylicacid t-butyl ester (0.179 g, 0.54 mmol) in EtOH (3 mL) and stirred atrt. An NaOEt solution (2.4 M in EtOH, 0.22 mL, 0.54 mmol) was added andthe reaction was stirred at rt for 20 h then at 50° for 9 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂; n-heptane/EtOAc 2:1) to give the title compound (0.116 g, 76%).

3β-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]octane

A reaction flask was charged with3β-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butylester (0.115 g, 0.41 mmol) in DCM (1 mL). TFA (0.2 mL) was added and thereaction was stirred at rt for 4 h. The reaction mixture wasconcentrated to give the TFA salt of the title compound (0.182 g)

3-Ethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride

To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(0.50 g, 2.2 mmol) dissolved in MeOH (10 ml) was addedo-ethyl-hydroxylamine hydrochloride (0.22 mg, 2.2 mmol) and the solutionwas stirred for 64 h at rt. The solution was concentrated under reducedpressure to yield the crude title compound that was used without furtherpurification.

3-Cyclopropylmethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride

To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(0.15 g, 0.65 mmol) dissolved in MeOH (10 ml) was addedO-cyclopropylmethyl-hydroxylamine (80 mg, 0.65 mmol). The solution wasconcentrated under reduced pressure to yield the crude title compoundthat was used without further purification.

General Procedure 2 (GP2)

A reaction flask or vial was charged 4H-benzo[1,4]oxazin-3-one (1.0equiv) dissolved in DMF (0.1 g/ml), Cs₂CO₃ (1.5 equiv) and1-chloro-3-iodopropane (1.1 equiv). The reaction was stirred in rt for60-70 h and evaporated to dryness. The reaction was redisolved in H₂Oand extracted with EtOAc 3×150 ml. The combined organic phases weredried over Na₂SO₄ and concentrated to a crude that was used directly orpurified by column chromatography (heptanes/EtOAc).

4-(3-Chloropropyl)-5,7-difluoro-4H-benzo[1,4]oxazin-3-one

5,7-Difluoro-4H-benzo[1,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs₂CO₃ (1.08g, 3.3 mmol), and 1-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixedaccording to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound(0.17 g, 49%). R_(f)=0.66 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H),2.21-2.10 (m, 2H).

4-(3-Chloropropyl)-5,8-difluoro-4H-benzo[1,4]oxazin-3-one

5,8-Difluoro-4H-benzo[1,4]oxazin-3-one (1.86 g, 10 mmol), Cs₂CO₃ (4.91g, 15 mmol), and 1-chloro-3-iodopropane (2.04 g, 10 mmol) were mixedaccording to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound(0.44 g, 17%). R_(f)=0.74 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d6.86-6.73 (m, 2H), 4.60 (s, 2H), 4.18-4.12 (m, 2H), 3.56 (t, J=6.4 Hz,2H), 2.20-2.12 (m, 2H); ¹³C NMR (CDCl₃) d 164.7, 148.4 (dd, J=243.9 Hz,J=2.8 Hz), 147.5 (dd, J=243.7 Hz, J=3.0 Hz), 136.6 (dd, J=16.2 Hz, J=5.0Hz), 119.8 (dd, J=11.2 Hz, J=2.7 Hz), 111.5 (dd, J=20.4 Hz, J=9.6 Hz),110.4 (dd, J=24.8 Hz, J=7.9 Hz), 68.6, 42.4 (d, J=10.0 Hz), 42.1, 31.1(d, J=3.5 Hz).

4-(3-Chloropropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one

8-Ethyl-4H-benzo[1,4]oxazin-3-one (0.35 g, 2.0 mmol), Cs₂CO₃ (0.96 g,2.9 mmol), and 1-chloro-3-iodopropane (0.45 g, 2.2 mmol) were mixedaccording to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound(0.38 g, 74%). R_(f)=0.64 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d7.01-6.89 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.62 (t, J=6.4 Hz,2H), 2.65 (q, J=7.6 Hz, 2H), 2.21-2.12 (m, 2H), 1.20 (t, J=7.6 Hz, 3H);¹³C NMR (CDCl₃) d 1.64.9, 143.3, 133.4, 128.4, 124.3, 122.6, 112.6,67.2, 42.5, 39.2, 30.3, 23.0, 14.5.

4-(3-Chloropropyl)-6,8-difluoro-4H-benzo[1.4]oxazin-3-one

6,8-Difluoro-4H-benzo[1,4]oxazin-3-one (0.80 g, 4.3 mmol), Cs₂CO₃ (2.12g, 6.5 mmol), and 1-chloro-3-iodopropane (0.98 g, 4.8 mmol) were mixedaccording to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound(0.44 g, 39%). R_(f)=0.65 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d6.66-6.59 (m, 2H), 4.64 (s, 2H), 4.09-4.03 (m, 2H), 3.62 (t, J=6.0 Hz,2H), 2.23-2.10 (m, 2H); ¹³C NMR (CDCl₃) d 164.2, 157.5 (dd, J=242.5 Hz,J=12.7 Hz), 151.7 (dd, J=248.5 Hz, J=14.4 Hz), 131.0 (dd, J=12.1 Hz,J=4.8 Hz), 130.4 (dd, J=15.0 Hz, J=3.2 Hz), 99.7 (dd, J=26.9 Hz, J=22.4Hz), 98.2 (dd, J=28.4 Hz, J=3.4 Hz), 67.8, 42.2, 39.7, 30.0.

4-(3-Chloropropyl)-5,6-difluoro-4H-benzo[1.4]oxazin-3-one

5,6-Difluoro-4H-benzo[1,4]oxazin-3-one (0.13 g, 0.69 mmol), Cs₂CO₃ (0.45g, 1.4 mmol), and 1-chloro-3-iodopropane (0.15 g, 0.76 mmol) were mixedaccording to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound(0.13 g, 75%). R_(f)=0.60 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d6.88-6.74 (m, 2H), 4.52 (s, 2H), 4.19-4.14 (m, 2H), 3.58 (t, J=6.4 Hz,2H), 2.22-2.14 (m, 2H); ¹³C NMR (CDCl₃) d 165.1, 147.5 (dd, J=242.5 Hz,J=12.7 Hz), 143.8 (t, J=3.0 Hz), 140.7 (dd, J=249.8 Hz, J=17.3 Hz),119.8 (d, J=4.6 Hz), 111.9 (dd, J=7.4 Hz, J=3.9 Hz), 111.2 (d, J=18.8Hz), 68.4, 42.4 (d, J=9.7 Hz), 42.1, 31.1 (d, J=3.5 Hz).

(R,S)-4-(3-Chloro-2-methylpropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one

8-Ethyl-4H-benzo[1,4]oxazin-3-one (0.34 g, 1.9 mmol), Cs₂CO₃ (0.94 g,2.9 mmol), and 1-bromo-3-chloro-2-methylpropane (0.36 g, 2.1 mmol) weremixed according to GP2. Purified by column chromatography (SiO₂;heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound(0.36 g, 69%). R_(f)=0.76 (heptanes/EtOAc 1:1).

4-(3-Chloropropyl)-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with 4H-benzo[1.4]oxazin-3-one (1.48 g, 10mmol), 1-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs₂CO₃ (4.88 g, 15mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixturewas quenched with water and the product extracted into EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂; n-heptane/EtOAc 2:1) to give the title compound (1.97 g, 88%). ¹HNMR (CDCl₃) d 7.06-7.02 (m, 2H), 7.01-6.99 (m, 2H), 4.58 (s, 2H),4.12-4.07 (m, 2H), 3.64-3.60 (m, 2H), 2.19-2.12 (m, 2); ¹³C NMR (CDCl₃)d 164.7, 145.6, 128.6, 124.2, 123.2, 117.5, 114.9, 67.8, 42.6, 39.1,30.3.

4-(3-Chloropropyl)-7-fluoro-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one(1.5 g, 8.1 mmol), 1-chloro-3-iodopropane (1.44 g, 8.1 mmol), and Cs₂CO₃(4.0 g, 12.2 mmol) in MeCN (10 mL) and stirred at rt for 40 h. Thereaction mixture was concentrated, water added, and the productextracted into EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The product was purified by flashcolumn chromatography (SiO₂; n-heptane/EtOAc 2:1) to give the titlecompound (1.88 g, 89%). ¹H NMR (CDCl₃) d 6.99 (dd, J=8.0 Hz, J=5.6 Hz,1H), 6.79-6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t,J=6.0 Hz, 2H) 2.18-2.10 (m, 2H); ¹³C NMR (CDCl₃) d 163.9, 159.1 (d,J=244.1 Hz), 146.4 (d, J=11.9 Hz), 124.9 (d, J=3.0 Hz), 115.4 (d, J=9.6Hz), 109.5 (d, J=22.7 Hz), 105.4 (d, J=26.2 Hz), 67.7, 42.4, 39.2, 30.1.

4-(3-Chloropropyl)-6-7-difluoro-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one(9.0 g, 54 mmol), 1-chloro-3-iodopropane (12.06 g, 59 mmol), and Cs₂CO₃(26.39 g, 81 mmol) in MeCN (150 mL) and stirred at rt for 40 h. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂; n-heptane/EtOAc 4:1) to give the title compound (11.35 g, 86%).¹H NMR (CDCl₃) d 6.93-6.82 (m, 2H), 4.57 (s, 2H), 4.05-4.01 (m, 2H),3.62 (t, J=6.1 Hz, 2H), 2.17-2.10 (m, 2H); HPLC-MS (ammonium acetate)[M+H]⁺=407.29

4-(3-Chloropropyl)-6-fluoro-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with 6-fluoro-4H-benzo[1.4]oxazin-3-one(1.67 g, 10 mmol), 1-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs₂CO₃(4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 3 days. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂; n-heptane/EtOAc 2:1) to give the title compound (145LH20) (2.32g, 95%). ¹H NMR (CDCl₃) d 6.95-6.91 (m, 1H), 6.82-6.78 (m, 1H),6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2Hz, 2H), 2.19-2.11 (m, 2H); ¹³C NMR (CDCl₃) d 164.6, 158.6 (d, J=240.7Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz),110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0.

(R,S)-4-(3-Chloro-2-methylpropyl)-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with 4H-benzo[1.4]oxazin-3-one (3.85 g,25.8 mmol), 1-bromo-3-chloro-2-methylpropane (4.42 g, 25.8 mmol), andCs₂CO₃ (12.4 g, 38 mmol) in MeCN (50 mL) and stirred at rt for 20 h. Thereaction mixture was quenched water and the product extracted intoEtOAc. The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by flash column chromatography(SiO₂;n-heptane; n-heptane/EtOAc 4:1) to give the crude title compound(5.62 g, 60% pure).

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (2.47 g,16.5 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (4.01g, 15.0 mmol), and Cs₂CO₃ (12.2 g, 37.6 mmol) in DMF (20 mL) and stirredat 55° for 20 h. The reaction mixture was quenched with water and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified byflash column chromatography (SiO₂; n-heptane/EtOAc 10:1) to give thetitle compound (3.92 g, 78%). ¹H NMR (CDCl₃) δ 7.15-7.11 (m, 1H),6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz,1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz,1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m,12H), 0.02 (s, 6H).

(R)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (1.49 g,10.0 mmol), (S)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (2.67g, 10.0 mmol), and Cs₂CO₃ (4.89 g, 15.0 mmol) in MeCN (15 mL) andstirred at rt for 7 days. The reaction mixture was quenched with waterand the product extracted into EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The product was purifiedby flash column chromatography (SiO₂; n-heptane/EtOAc 2:1) to give thetitle compound (2.84 g, 85%).

(S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(3.92 g, 11.7 mmol), and TBAF (4.78 g, 15.2 mmol) in THF (30 mL) andstirred at rt for 20 h. The reaction mixture was concentrated, dissolvedin EtOAc, and washed with brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The product was purified by flashcolumn chromatography (SiO₂; n-heptane/EtOAc 3:7) to give the titlecompound (2.52 g, 98%). ¹H NMR (CDCl₃) δ 7.05-6.95 (m, 4H), 4.63 (s,CH₂), 4.23 (dd, J=10.3 Hz, J=13.9 Hz, 1H), 3.56 (dd, J=4.8 Hz, J=13.9Hz, 1H), 3.52-3.49 (m, 1H), 3.46-3.38 (m, 1H), 2.92-2.85 (m, 1H),2.09-1.97 (m, 1H), 1.06 (d, J=7.3 Hz, CH₃).

(R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with(R)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(2.83 g, 8.5 mmol), and TBAF (11 mL, 1.0 M in THF, 11.0 mmol) in THF (10mL) and stirred at rt for 20 h. The reaction mixture was concentrated,dissolved in EtOAc, and washed with brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated. The product was purified byflash column chromatography (SiO₂; n-heptane/EtOAc 1:1) to give thetitle compound (1.72 g, 91%).

(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with(S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (2.52 g, 11.4mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1mmol), and iodine (8.88 g, 35.0 mmol) in CHCl₃ (30 mL) and stirred at rtfor 20 h. The reaction mixture was washed with saturated sodiumthiosulfate, dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash column chromatography (SiO₂; n-heptane/EtOAc 3:1)to give the title compound (3.02 g, 80%). ¹H NMR (CDCl₃) δ 7.07-7.00 (m,4H), 4.65-4.55 (m, 2H), 3.94 (dd, J=1.7 Hz, J=6.7 Hz, CH₂), 3.23-3.14(m, 2H), 2.18-2.07 (m, 1H), 1.05 (d, J=6.1 Hz, CH₃).

(R)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with(R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.71 g, 7.77mmol), triphenylphosphine (4.50 g, 17.2 mmol), imidazole (1.27, 18.7mmol), and iodine (5.54 g, 21.8 mmol) in CH₂Cl₂ (20 mL) and stirred atrt for 20 h. The reaction mixture was washed with saturated sodiumthiosulfate, dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash column chromatography (SiO₂; n-heptane/EtOAc 2:1)to give the title compound (2.25 g, 87%).

(R,S)-4-[3-(t-Butyldimethylsilanyloxy)-2-hydroxypropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with 7-fluoro-4H-benzo[1,4]oxazin-3-one(3.34 g, 20.0 mmol), t-butyldimethylsilyl glycidyl ether (4.685 g, 24.9mmol), and Cs₂CO₃ (9.75 g, 29.9 mmol) in MeCN (25 mL) and stirred at rtfor 20 h. The reaction mixture was quenched with water and the productextracted into EtOAc. The organic layer was dried over Na₂SO₄, filtered,and concentrated. The product was purified by flash columnchromatography (SiO₂; n-heptane/EtOAc 2:1) to give crude the titlecompound (2.048 g). ¹H NMR (CDCl₃) d 7.15-7.11 (m, 1H), 6.68-6.62 (m,2H), 4.46 (s, 2H), 4.00-3.88 (m, 3H), 3.61-3.58 (m, 2H), 3.02-2.98 (m,1H), 0.86 (s, 9H), 0.03 (s, 6H).

(R,S)-4-[3-(t-Butyldimethylsilanyloxy)-2-methoxypropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one

A reaction flask was charged with crude(R,S)-4-[3-(t-butyldimethylsilanyloxy)-2-hydroxypropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one(2.04 g) in dry THF (10 mL) under Argon. NaH (60% in oil, 0.230 g, 5.76mmol) was added in portions and the mixture was stirred at 0° for 1 hunder Argon. Iodomethane (0.818 g g, 5.76 mmol) was added at 0° understirring. The temperature was slowly raised to rt and the reaction wasstirred for 20 h under Argon. The reaction mixture was quenched withwater and the product extracted into EtOAc. The combined organic phaseswere dried over Na₂SO₄, filtered, and concentrated. The product waspurified by flash column chromatography (SiO₂; n-heptane/EtOAc 2:1) togive the crude title compound (1.026 g).

(R,S)-7-Fluoro-4-(3-hydroxy-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with crude(R,S)-4-[3-(t-Butyldimethylsilanyloxy)-2-methoxypropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one(1.026 g), and TBAF (0.940 g, 36.0 mmol) in THF (10 mL) and stirred atrt for 20 h. The reaction mixture was concentrated, dissolved in EtOAc,and washed with brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The product was purified by flash columnchromatography (SiO₂; n-heptane/EtOAc 1:1) to give the crude titlecompound (0.503 g). ¹H NMR (CDCl₃) d 7.26-7.20 (m, 1), 6.76-6.70 (m,2H), 4.65-4.56 (m, 2H), 4.14-4.09 (m, 1H), 4.04-3.97 (m, 1H), 3.75-3.70(m, 1H), 3.60-3.53 (m, 2H), 3.42 (s, H).

(R,S)-7-Fluoro-4-(3-iodo-2-methoxypropyl)-4H-benzo1.4]oxazin-3-one

A reaction flask was charged with crude7-fluoro-4-((R,S)-3-hydroxy-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one(0.503 g), triphenylphosphine (1.14 g, 4.33 mmol), imidazole (0.322 g,4.73 mmol), and iodine (1.40 g, 5.52 mmol) in DCM (5 mL) and stirred atrt for 20 h. The reaction mixture was added DCM, washed with saturatedsodium thiosulfate, dried over Na₂SO₄, filtered, and concentrated. Theproduct was purified by flash column chromatography (SiO₂;n-heptane/EtOAc 2:1) to give the crude title compound (0.668 g).

General Procedure 3 (GP3)

A reaction flask or vial was charged with 4-cyclopropylmethoxypiperidine(1.0-1.05 equiv) dissolved in dry acetonitrile (0.1 g/ml),4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (1.0 equiv), K₂CO₃ (2.0equiv), and NaI (2.0 equiv) and stirred or shaken at 60° C. for 40-48 h.The reaction mixture was evaporated to dryness and purified by columnchromatography (heptanes/EtOAc) or (CH₂Cl₂/MeOH) or Prep TLC(heptanes/EtOAc) or (CH₂Cl₂/MeOH).

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(AC00262469)

4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol),4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.08 g, 0.32mmol), K₂CO₃ (0.075 g, 0.54 mmol) and KI (0.081 g, 0.54 mmol) were mixedaccording to GP3. Purified by prep TLC (SiO₂; heptanes/EtOAc 1:1) togive the title compound (0.049 g, 42%). R_(f)=0.47 (CH₂Cl₂/MeOH 10:1);¹H NMR (CDCl₃) d 7.09-7.04 (m, 1H), 6.75-6.69 (m, 2H), 4.57 (s, 2H),3.95 (t, J=7.2 Hz), 3.34-3.25 (m, 3H), 2.77-2.70 (m, 2H), 2.36 (t, J=6.8Hz, 2H), 2.11-2.02 (m, 2H), 1.93-1.76 (m, 4H), 1.64-1.54 (m, 2H),1.09-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.21-0.16 (m, 2H); ¹³C NMR (CDCl₃)d 163.6, 158.9 (d, J=243.7 Hz), 146.3 (d, J=11.6 Hz), 125.2 (d, J=3.1Hz), 115.8 (t, J=11.2 Hz), 109.2 (d, J=22.3 Hz), 105.2 (dd, J=25.7 Hz,J=3.8 Hz), 75.0, 72.8, 67.8 (t, J=8.1 Hz), 55.4, 51.6 (J=9.2 Hz), 39.9(t, J=12.3 Hz), 31.7, 24.9, 11.1, 3.2.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.057 g); HPLC-MS (ammoniumacetate) [M+H]⁺=363.30; Mp 170.3-171.3° C.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-5,7-difluoro-4H-benzo[1,4]oxazin-3-one(AC00262471)

4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol),4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.078 g, 0.30mmol), K₂CO₃ (0.075 g, 0.54 mmol), and KI (0.081 g, 0.54 mmol) weremixed according to GP3. Purified by prep TLC (SiO₂; heptanes/EtOAc 1:1)to give the title compound (0.039 g, 38%). R_(f)=0.47 (CH₂Cl₂/MeOH10:1); ¹H NMR (CDCl₃) d 6.61-6.54 (m, 2H), 4.50 (s, 2H), 4.05-4.00 (m,2H), 3.30-3.23 (m, 3H), 2.72-2.65 (m, 2H), 2.31 (t, J=7.2 Hz, 2H),2.05-1.96 (m, 2H), 1.87-1.74 (m, 4H), 1.60-1.49 (m, 2H), 1.07-0.96 (m,1H), 0.53-0.48 (m, 2H), 0.19-0.14 (m, 2H); ¹³C NMR (CDCl₃) d 164.4,158.5 (dd, J=245.5 Hz, J=15.0 Hz,), 151.7 (dd, J=249.1 Hz, J=14.2 Hz),149.5 (q, J=6.9 Hz), 115.1 (dd, J=10.0 Hz, J=4.6 Hz), 101.5 (dd, J=25.8Hz, J=3.5 Hz), 99.7 (t, J=26.9 Hz), 75.0, 72.7, 68.6 (t, J=5.3 Hz),55.6, 51.5 (d, J=9.7 Hz), 42.7 (q, J=10.4 Hz), 31.5, 25.6 (d, J=2.3 Hz),11.1, 3.2.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.044 g); HPLC-MS (ammoniumacetate) [M+H]⁺=381.28.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-5,6-difluoro-4H-benzo[1,4]oxazin-3-one(AC00262696)

4-Cyclopropylmethoxypiperidine (0.037 g, 0.24 mmol),4-(3-chloropropyl)-5,6-difluoro-4H-benzo[1,4]oxazin-3-one (0.065 g, 0.25mmol), K₂CO₃ (0.06 g, 0.48 mmol), and KI (0.072 g, 0.48 mmol) were mixedaccording to GP3. Purified by prep TLC (SiO₂; heptanes/EtOAc 1:1) togive the title compound (0.049 g, 54%). R_(f)=0.21 (heptanes/EtOAc 1:1);¹H NMR (CDCl₃) d 6.84-6.70 (m, 2H), 4.48 (s, 2H), 4.48 (s, 2H),4.08-4.02 (m, 2H), 3.34-3.26 (m, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.75-2.68(m 2H), 2.38 (t, J=7.2 Hz, 2H), 2.18-2.06 (m, 2H), 1.92-1.81 (m, 4H),1.63-1.52 (m, 2H), 1.06-0.96 (m, 2H), 0.52-0.47 (m, 2H), 0.18-0.14 (m,2H); ¹³C NMR (CDCl₃) d 165.0, 147.5 (dd, J=242.3 Hz, J=13.2 Hz), 143.9,140.7 (dd, J=250.2 Hz, J=17.3 Hz), 119.9, 111.7 (dd, J=7.3 Hz, J=3.5Hz), 110.9 (d, J=18.9 Hz), 74.5, 72.7, 68.5, 55.5, 51.2, 42.7 (d, J=10.4Hz), 31.1, 25.5, (d, J=2.6 Hz), 11.1, 3.2.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.052 g); HPLC-MS (ammoniumacetate) [M+H]⁺=381.35.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl1propyl]-6,8-difluoro-4H-benzo[1,4]oxazin-3-one(AC00262874)

4-Cyclopropylmethoxypiperidine (0.076 g, 0.49 mmol),4-(3-chloropropyl)-6,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.143 g, 0.55mmol), K₂CO₃ (0.136 g, 0.98 mmol) and KI (0.147 g, 0.98 mmol) were mixedaccording to GP3. Purified by prep TLC (SiO₂; heptanes/EtOAc 1:1) togive the title compound (0.094 g, 50%). ¹H NMR (CDCl₃) d 6.83-6.78 (m,1H), 6.60-6.54 (m, 1H), 4.60 (s, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.36-3.24(m, 3H), 2.77-2.68 (m, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.09 (t, J=9.6 Hz,2H), 1.93-1.76 (m, 4H), 1.66-1.56 (m, 2H), 1.08-0.97 (m, 1H), 0.53-0.48(m, 2H), 0.19-0.15 (m, 2H); ¹³C NMR (CDCl₃) d 163.9, 157.4 (dd, J=241.4Hz, J=12.7 Hz), 151.4 (dd, J=247.6 Hz, J=14.3 Hz), 131.4 (dd, J=12.5 Hz,J=4.7 Hz), 130.2 (dd, J=14.6 Hz, J=3.9 Hz), 99.3 (dd, J=26.9 Hz, J=22.3Hz), 98.6 (dd, J=28.4 Hz, J=3.5 Hz), 74.8, 72.8, 67.8, 55.1, 51.5, 40.3,31.5, 24.8, 11.1, 3.2.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.099 g); HPLC-MS (ammoniumacetate) [M+H]⁺=381.33.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-5,8-difluoro-4H-benzo[1,4]oxazin-3-one(AC00262869)

4-Cyclopropylmethoxypiperidine (0.085 g, 0.55 mmol),4-(3-chloropropyl)-5,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.146 g, 0.56mmol), K₂CO₃ (0.152 g, 1.1 mmol), and KI (0.164 g, 1.1 mmol) were mixedaccording to GP3. Purified by prep TLC (SiO₂; Heptanes/EtOAc 1:1) togive the title compound (0.078 g, 37%). ¹H NMR (CDCl₃) d 6.82-6.69 (m,2H), 4.57 (s, 2H), 4.07-4.03 (m, 2H), 3.31-3.22 (m, 3H), 2.72-2.64 (m,2H), 2.32 (t, J=7.2 Hz, 2H), 2.02 (t, J=10.4 Hz, 2H), 1.88-1.76 (m, 4H),1.59-1.48 (m, 2H), 1.07-0.95 (m, 2H), 0.53-0.47 (m, 2H), 0.19-0.14 (m,2H); ¹³C NMR (CDCl₃) d 164.6, 148.3 (dd, J=243.3 Hz, J=2.7 Hz), 147.7(dd, J=243.9, J=2.8 Hz), 136.6 (dd, J=11.2Hz, J=4.9Hz), 120.0 (d, J=11.1Hz), 111.2 (dd, J=20.4Hz, J=9.6 Hz), 110.3 (dd, J=24.8 Hz, J=7.7 Hz),75.0, 72.6, 68.6, 55.6, 51.5, 42.7 (d, J=10.8 Hz), 31.5, 25.7 (d, J=2.7Hz), 11.1, 3.2.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.075 g); HPLC-MS (ammoniumacetate) [M+H]⁺=381.33.

(R,S)-4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)-2-methylpropyl]-8-ethyl-4H-benzo[1,4]oxazin-3-one(AC00262867)

4-Cyclopropylmethoxypiperidine (0.091 g, 0.59 mmol),(R,S)-4-(3-Chloro-2-methylpropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one(0.175 g, 0.65 mmol), K₂CO₃ (0.162 g, 1.2 mmol), and KI (0.176 g, 1.2mmol) were mixed according to GP3. Purified by prep TLC (SiO₂;heptanes/EtOAc 1:1) to give the title compound (0.055 g, 24%).R_(f)=0.29 (heptanes/EtOAc 1:1); ¹H NMR (CDCl₃) d 7.02-6.85 (m, 3H),4.66-4.49 (m, 2H), 4.04-3.90 (m, 2H), 3.33-3.24 (m, 3H), 2.84-2.78 (m,1H), 2.68-2.60 (m, 3H), 2.28-1.8 (m, 7H), 1.65-1.52 (m, 2H), 1.28-1.16(m, 3H), 1.10-0.98 (m, 1H), 0.88 (d, J=6.4 Hz, 3H), 0.56-0.50 (m, 2H),0.21-0.16 (m, 2H); ¹³C NMR (CDCl₃) d 165.1, 143.5, 133.1, 128.7, 123.9,122.2, 113.4, 75.3, 72.7, 67.8, 63.5, 52.9, 51.9, 45.4, 31.9, 31.8,29.4, 23.0, 16.9, 14.5, 11.1, 3.2

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.055 g); HPLC-MS (ammoniumacetate) [M+H]⁺=387.40.

4-[3-(3-Cyclopropylmethoxy-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-8-ethyl-4H-benzo[1,4]oxazin-3-one (00264438)

A 7 ml vial was charged with4-(3-chloropropyl)-8-ethyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.83mmol), 3-cyclopropylmethoxy-8-aza-bicyclo[3,2,1]octane (0.16 g, 0.87mmol), K₂CO₃ (0.23 g, 1.7 mmol), acetonitrile (4 ml) a shaken at 60° C.for 90 hours The reaction mixture was evaporated to dryness and purifiedby prep TLC (SiO₂; heptanes/EtOAc 1:1) followed by Prep HPLC to give thetitle compound (0.068 g, 20.5%). ¹H NMR (CDCl₃) ¹H NMR (CDCl₃) d7.05-6.84 (m, 3H), 4.56 (s, 2H), 4.04-3.98 (m, 2H), 3.53-3.49 (m, 1H),3.19-3.11 (m, 4H), 2.67-2.59 (m,2H), 2.42-2.37 (m, 2H), 2.07-1.74 (m,1OH), 1.21-1.15 (m, 3H), 1.06-0.93 (m, 1H), 0.51-0.44 (m, 2H), 0.21-0.14(m, 2H); ¹³C NMR (CDCl₃) d 164.60, 143.25, 133.02, 128.66, 123.99,122.32, 113.20, 72.78, 72.23, 67.74, 58.59, 49.56, 39.83, 35.73, 26.45,26.17, 23.03, 14.50, 11.04, 2.94.

The product was dissolved in ether and oxalic acid dissolved in etherwas added. The formed crystals were filtered and washed with ether togive the title compound as oxalic salt (0.075 g); HPLC-MS (ammoniumacetate) [M+H]⁺=399.52.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-4H-benzo[1.4]oxazin-3-one(AC00262922)

A 4 mL vial was charged with4-(3-chloropropyl)-4H-benzo[1,4]oxazin-3-one (0.068 g, 0.3 mmol),4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), NaI (0.075 g, 0.5mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in MeCN (1 mL) and shaken at 50°for 20 h. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography to give the title compound (0.076 g,74%). ¹H NMR (CDCl₃) d 6.96-6.93 (m, 1H), 6.87-6.80 (m, 3H), 4.41 (s,2H), 3.81 (t, J=7.4 Hz, 2H), 3.16-3.10 (m, 1H), 3.11 (d, J=6.8 Hz, 2H),2.62-2.57 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 1.94-1.89 (m, 2H), 1.75-1.64(m, 4H), 1.48-1.39 (m, 2H), 0.89-0.86 (m, 1H), 0.38-0.33 (m, 2H),0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 164.2, 145.3, 128.6, 123.7, 122.7,117.0, 115.0, 74.8, 72.6, 67.6, 55.3, 51.4, 39.5, 31.5, 24.8, 11.0, 3.0.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.078 g). HPLC-MS(ammonium acetate) [M+H]⁺=344.00.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one(AC00262635)

A 4 mL vial was charged with4-(3-chloropropyl)-6-fluoro-4H-benzo[1,4]oxazin-3-one (0.097 g, 0.4mmol), 4-cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), NaI (0.075g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in MeCN (1 mL) and shaken at50° for 20 h. The reaction mixture was quenched with water and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified bycation exchange column chromatography followed by flash columnchromatography (SiO₂; EtOAc) to give the title compound (0.056 g, 57%).¹H NMR (CDCl₃) d 6.80-6.71 (m, 2H), 6.52-6.47 (m, 1H), 4.38 (s, 2H),3.77 (t, J=7.2 Hz, 2H), 3.17-3.13 (m, 1H), 3.11 (d, J=6.8 Hz, 2H),2.59-2.56 (m, 2H), 2.19 (t, J=6.8 Hz, 2H), 1.95-1.89 (m, 2H), 1.75-1.62(m, 4H), 1.50-1.41 (m, 2H), 0.89-0.86 (m, 1H), 0.38-0.33 (m, 2H),0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 164.1, 158.3, 141.2, 129.8, 117.4,109.4, 102.9, 74.7, 72.5, 67.6, 55.1, 51.4, 39.8, 31.3, 24.6, 10.9, 3.0.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.062 g). HPLC-MS(ammonium acetate) [M+H]⁺=363.38.

4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-4H-benzo[1.4]oxazin-3-one(AC00262461)

A 4 mL vial was charged with4-(3-chloropropyl)-6,7-difluoro-4H-benzo[1,4]oxazin-3-one (0.077 g, 0.3mmol), 4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), NaI (0.075 g,0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at60° for 20 h. The reaction mixture was quenched with water and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified bycation exchange column chromatography followed by flash columnchromatography (SiO₂; EtOAc) to give the title compound (0.050 g, 44%).¹H NMR (CDCl₃) d 6.98-6.93 (m, 1H), 6.66-6.62 (m, 1H), 4.39 (s, 2H),3.74 (t, J=7.2 Hz, 2H), 3.20-3.15 (m, 1H), 3.11 (d, J=6.9 Hz, 2H),2.61-2.55 (m, 2H), 2.21 (t, J=6.8 Hz, 2H), 2.00-1.96 (m, 2H), 1.79-1.63(m, 4H), 1.52-1.46 (m, 2H), 0.89-0.85 (m, 1H), 0.38-0.33 (m, 2H),0.04-0.00 (m, 2H).

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.052 g). HPLC-MS(ammonium acetate) [M+H]⁺=381.30.

4-[3-(3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]oct-8-yl)propyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one(AC00262571)

A 4 mL vial was charged with4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.077 g, 0.3mmol), 3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.054 g, 0.3mmol), NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in MeCN(0.5 mL) and shaken at 50° for 20 h. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by cation exchange column chromatography to give the titlecompound (0.065 g, 56%). ¹H NMR (CDCl₃) d 7.00-6.96 (m, 1H), 6.57-6.53(m, 2H), 4.41 (s, 2H), 3.84 (t, J=7.2 Hz, 2H), 3.35 (t, J=4.9 Hz, 1H),3.03 (d, J=6.5 Hz, 2H), 2.97-2.88 (m, 2H), 2.22 (t, J=6.9 Hz, 2H),1.87-1.84 (m, 2H), 1.75-1.58 (m, 8H), 0.85-0.81 (m, 1H), 0.34-0.29 (m,2H), 0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 163.4, 158.7 (d, J=243.7 Hz),146.1 (d, J=11.5 Hz), 125.1 (d, J=3.1 Hz), 115.8 (d, J=9.2 Hz), 108.9(d, J=22.7 Hz), 104.9 (d, J=26.1 Hz), 72.6, 72.1, 67.6, 58.5, 49.3,39.7, 35.7, 26.2, 26.0, 10.9, 2.7.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.065 g). HPLC-MS(ammonium acetate) [M+H]⁺=389.30.

4-[3-(3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6.7-difluoro-4H-benzo[1.4]oxazin-3-one(AC00262569)

A 4 mL vial was charged with4-(3-chloropropyl)-6,7-difluoro-4H-benzo[1,4]oxazin-3-one (0.078 g, 0.3mmol), 3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.054 g, 0.3mmol), NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in MeCN(0.5 mL) and shaken at 50° for 20 h. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by cation exchange column chromatography to give the titlecompound (0.073 g, 60%). ¹H NMR (CDCl₃) d 7.14-7.09 (m, 1H), 6.66-6.61(m, 1H), 4.39 (s, 2H), 3.80 (t, J=7.0 Hz, 2H), 3.36 (t, J=5.1 Hz, 1H),3.03 (d, J=6.5 Hz, 2H), 2.93 (br s, 2H), 2.19 (t, J=6.5 Hz, 2H),1.88-1.83 (m, 2H), 1.80-1.74 (m, 2H), 1.68-1.57 (m, 6H), 0.85-0.81 (m,1H), 0.34-0.29 (m, 2H), 0.04-0.00 (m, 2H).

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.071 g). HPLC-MS(ammonium acetate) [M+H]⁺=407.29.

(R,S)-4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(AC00262273)

A 4 mL vial was charged with(R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (0.120 g,60% pure, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.042 g, 0.27mmol), NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in DMF (1mL) and shaken at 50° for 20 h. The reaction mixture was quenched withwater and the product extracted into EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. The product waspurified by cation exchange column chromatography followed by flashcolumn chromatography (SiO₂; EtOAc) to give the title compound (0.063 g,67%). ¹H NMR d (CDCl₃) d 6.99-6.97 (m, 1H), 6.85-6.79 (m, 3H), 4.48-4.36(m, 2H), 3.85-3.75 (m, 2H), 3.14-3.10 (m, 2H), 2.64-2.62 (m,1H),2.49-2.46 (m, 1H), 2.10-1.68 (m, 7H), 1.46-1.39 (m, 2H), 0.89-0.85 (m,1H), 0.71 (d, J=6.7 Hz, 3H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H); ¹³CNMR (CDCl₃) d 164.7, 145.5, 128.6, 123.5, 122.5, 117.0, 115.4, 75.1,72.6, 67.6, 63.3, 52.7, 51.7, 45.1, 31.7, 31.6, 29.2, 16.8, 11.0, 3.0.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.060 g). HPLC-MS(ammonium acetate) [M+H]⁺=359.31.

4-[(R,S)-3-(4-Cyclobutylmethoxypiperidin-1-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one(AC00262197) and carbonic acid cyclobutylmethyl ester1-[(R,S)-2-methyl-3-(3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-yl)propyl]piperidine-4-ylester (AC00262198)

A 4 mL vial was charged with4-((R,S)-3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (0.120 g,60% pure 0.3 mmol), a mixture of 4-cyclobutylmethoxypiperidine andcarbonic acid cyclobutylmethyl ester piperidine-4-yl ester (0.051 g),NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in DMF (1 mL) andshaken at 95° for 3 days. The reaction mixture was quenched with waterand the products extracted into EtOAc. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The products werepurified by cation exchange column chromatography followed by flashcolumn chromatography (SiO₂; n-heptane/EtOAc 1:1) to give the titlecompounds4-[(R,S)-3-(4-Cyclobutylmethoxypiperidin-1-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one(0.033 g) and carbonic acid cyclobutylmethyl ester1-[(R,S)-2-methyl-3-(3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-yl)propyl]piperidine-4-ylester (0.014 g).

Data of4-[(R,S)-3-(4-Cyclobutylmethoxypiperidin-1-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one:¹H NMR (CDCl₃) d 7.16-7.14 (m, 1H), 7.02-6.96 (m, 3H), 4.65-4.60 (m,2H), 4.11-3.91 (m, 2H), 3.41 (d, J=6.9 Hz), 3.27-3.22 (m, 1H), 2.80-2.77(m, 1H), 2.26-1.82 (m, 11H), 1.75-1.68 (m, 2H), 1.61-1.54 (m, 2H), 0.88(d, J=6.7 Hz, 3H); ¹³C NMR (CDCl₃) d 164.7, 145.5, 128.7, 123.6, 122.5,117.0, 115.4, 75.3, 72.6, 67.6, 63.4, 52.7, 51.7, 45.1, 35.4, 31.7,31.6, 29.3, 25.1, 18.6, 16.8.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.034 g). HPLC-MS(ammonium acetate) [M+H]⁺=373.23.

Data of carbonic acid cyclobutylmethyl ester1-[(R,S)-2-methyl-3-(3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-yl)propyl]piperidine-4-ylester: ¹H NMR (CDCl₃) d 7.13-7.09 (m, 1H), 7.02-6.96 (m, 3H), 4.64-4.54(m, 2H), 4.10 (d, 2H), 3.98-3.94 (m, 2H), 2.78-2.56 (m, 3H), 2.30-1.68(m, 17H), 0.90 (d, 2H); ¹³C NMR (CDCl₃) d 164.7, 154.9, 145.6, 128.7,123.6, 122.5, 117.2, 115.3, 74.3, 71.7, 67.7, 63.3, 51.8, 51.2, 45.2,34.1, 31.1, 30.9, 29.1, 24.7, 18.4, 16.8.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.010 g). HPLC-MS(ammonium acetate) [M+H]⁺=417.20.

(R,S)-4-[3-(3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one(AC00262573)

A 4 mL vial was charged with(R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one. (0.120 g,60% pure, 0.3 mmol), 3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane(0.054 g, 0.3 mmol), NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5mmol) in MeCN (0.5 mL) and shaken at 50° for 20 h. The reaction mixturewas quenched with water and the product extracted into EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by cation exchange columnchromatography followed by flash column chromatography (SiO₂; EtOAc) togive the title compound (0.067 g, 58%). ¹H NMR (CDCl₃) d 7.10-7.07 (m,1H), 6.84-6.79 (m, 3H), 4.49-4.36 (m, 2H), 3.89-3.84 (m, 2H), 3.34 (t,J=4.9 Hz, 1H), 3.02 (d, J=6.5 Hz, 2H), 2.92-2.90 (m, 1H), 2.84-2.82 (m,1H), 2.16-2.11 (m, 1H), 1.95-1.89 (m, 1H), 1.83-1.58 (m, 9H), 0.85-0.81(m, 1H), 0.70 (d, J=6.7 Hz, 3H), 0.34-0.29 (m, 2H), 0.04-0.00 (m, 2H);¹³C NMR (CDCl₃) d 164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.7, 72.6,72.2, 67.6, 60.4, 58.7, 58.2, 45.0, 36.2, 36.1, 31.3, 26.7, 25.7, 16.8,10.9, 2.7.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.073 g). HPLC-MS(ammonium acetate) [M+H]⁺=385.35

4-{(R,S)-3-[3-(2-Cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00262357) (Diastereoisomers)

A 4 mL vial was charged with with4-((R,S)-3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (0.120 g,60% pure, 0.3 mmol),3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane (0.041 g,0.2 mmol), NaI (0.075 g, 0.5 mmol), and K₂CO₃ (0.069 g, 0.5 mmol) in DMF(1 mL) and stirred at 95° for 2 days. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by cation exchange column chromatography followed by flashcolumn chromatography (SiO₂; EtOAc; EtOAc/MeOH 10:1) to give the titlecompound as a diastereoisomeric mixture (0.044 g, 51%). ¹H NMR (CDCl₃) d7.19-7.19 (m, 1H), 7.00-6.90 (m, 3H), 5.37-5.34 (m, 1H), 4.59-4.46 (m,2H), 4.01-3.88 (m, 4H), 3.19-3.06 (m, 4H), 2.47-2.11, 1.93-1.70,1.47-1.31 (m, 9H), 1.02-0.96 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.48-0.44(m, 2H), 0.15-0.12 (m, 2H); ¹³C NMR (CDCl₃) d 164.7, 145.5, 137.9,128.7, 128.6, 123.5, 123.3, 122.4, 117.0, 115.7, 74.8, 67.7, 67.6, 67.6,66.1, 66.0, 61.3, 61.1, 60.2, 59.9, 57.3, 45.0, 41.8, 41.6, 34.8, 34.7,31.2, 27.5, 27.2, 26.6, 26.2, 16.8, 10.7, 3.00.

The diastereoisomeric mixture was dissolved in acetone and 1.1 equivoxalic acid dissolved in acetone was added. The formed crystals werefiltered and washed with acetone to give the title compound as oxalicsalt (0.042 g). HPLC-MS (ammonium acetate) [M+H]⁺=411.31.

4-[(R)-3-(4-Cyclopropylmethoxypiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(AC00262908)

A reaction flask was charged with(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.6mmol), 4-cyclopropylmethoxypiperidine (0.093 g, 0.6 mmol), and K₂CO₃(0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. Thereaction mixture was quenched with water and the product extracted intoEtOAc. The combined organic phases were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by cation exchange columnchromatography followed by flash column chromatography (SiO₂; EtOAc) togive the title compound (0.138 g, 64%). ¹H NMR (CDCl₃) d 6.99-6.97 (m,1H), 6.85-6.79 (m, 3H), 4.47-4.35 (m, 2H), 3.85-3.74 (m, 2H), 3.14-3.08(m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.64-2.61 (m, 1H), 2.49-2.46 (m, 1H),2.10-2.04 (m, 2H), 2.00-1.68 (m, 6H), 1.47-1.38 (m, 2H), 0.90-0.84 (m,1H), 0.71 (d, J=6.6 Hz, 3H), 0.37-0.33 (m, 2H), 0.04-0.00 (m, 2H); ¹³CNMR (CDCl₃) d 164.6, 145.4, 128.5 123.4, 122.4, 116.9, 115.3, 75.0,72.5, 67.5, 63.3, 52.6, 51.6, 45.0, 31.6, 31.5, 29.1, 16.7, 10.9, 2.9.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.172 g). HPLC-MS(ammonium acetate) [M+H]⁺=359.35.

(R)-4-[3-(3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one(AC00262909)

A reaction flask was charged with(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.6mmol), 3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.109 g, 0.6mmol), and K₂CO₃ (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50°for 3 days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography followed by flash column chromatography(SiO₂; EtOAc) to give the title compound (0.137 g, 59%). ¹H NMR (CDCl₃)d 7.10-7.07 (m, 1H), 6.86-6.80 (m, 3H), 4.49-4.36 (m, 2H), 3.88 (t,J=3.9 Hz, 2H), 3.34 (t, J=4.9 Hz, 1H), 3.02 (d, J=6.5 Hz, 2H), 2.91-2.83(m, 2H), 2.16-2.12 (m, 1H), 1.92-1.89 (m, 1H), 1.1.83-1.59 (m, 9H),0.85-0.81 (m, 1H), 0.71 (d, J=6.7 Hz, 3H), 0.34-0.29 (m, 2H); 0.04-0.00(m, 2H); ¹³C (CDCl₃) d 164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.8,72.6, 72.2, 67.6, 60.4, 58.7, 58.2, 45.1, 36.2, 36.1, 31.3, 26.7, 25.7,16.8, 10.9, 2.8.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.138 g). HPLC-MS(ammonium acetate) [M+H]⁺385.37.

(R)-4-[3-(3β-Butyl-3a-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methyl-propyl]-1H-benzo[1,4]oxazin-3-one(AC00261478)

A 7 ml vial was charged with 3-β-butyl-8-aza-bicyclo[3.2.1]octan-3a-ol(37 mg, 0.20 mmol),4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (130 mg, 0.40mmol), and Cs₂CO₃ (200 mg, 0.6 mmol) in dry DMF (4 ml) and the reactionwas shaken at 50° C. for 4 days. The reaction was then poured into waterand extracted with ether. The combined organic phases were washed withbrine, dried (Na₂SO₄), filtered, concentrated under reduced pressure andthe oily residue was purified by flash column chromatography (SiO₂;EtOAc/MeOH 95:5) to yield the title compound as an oil (63 mg, 16 mmol,82%). ¹H NMR (CDCl₃) d 7.28-7.21 (m, 1H), 7.02-6.95 (m, 3H), 4.60 (ABq,J=14.8, 34.0 Hz, 2H), 6.04 (d, J=6.8 Hz, 2H), 3.17-3.04 (m, 2H), 2.32dd, J=4.4, 12.8 Hz, 1H), 2.13 (dd, J=9.2, 12.8 Hz, 1H), 2.08-1.76 (m,7H), 1.62-1.51 (m, 2H), 1.38-1.24 (m, 6H), 0.94-0.86 (m, 6H);¹³C NMR(CDCl₃) d 164.9, 145.7, 129.0, 123.8, 122.6, 117.2, 115.9, 71.1, 67.9,60.7, 59.0, 58.1, 46.9, 45.4, 44.1, 31.6, 26.7, 25.7, 25.1, 23.4, 17.1,14.3; HPLC-MS (ammonium acetate) [M+H]⁺=359.46.

4-[3-(3-Ethoxyimino-8-aza-bicyclo[3.2.1]oct-8-yl)-2(R)-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(AC00261354)

A 7 ml vial was charged with4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (330 mg, 1.0mmol), crude 3-ethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride (200mg, 0.98 mmol), and K₂CO₃ (290 mg, 2.1 mmol) in dry DMF (4 ml) and thereaction was shaken at 60° C. for 3 days. The reaction was then pouredinto water and extracted with ether. The combined organic phases werewashed brine, dried (Na₂SO₄), filtered, concentrated under reducedpressure and the oily residue was purified by flash columnchromatography (SiO₂; CH₂Cl₂/acetone/MeOH, 90:7:3) to yield thediastereomeric mixture of the title compound as an oil (87 mg, 0.24mmol, 24%). ¹H NMR (CD₃OD) d 7.28 (dd, J=2.0, 7.6 Hz, 1H), 7.07-6.93 (m,3H), 4.57 (ABq, J=14.8, 19.6 Hz, 2H), 4.12 (dd, J=6.4, 14.4 Hz, 1H),4.05-3.92 (m, 3H), 3.30-3.16 (m, 2H), 2.92-2.82 (m, 1 H), 2.54-2.32 (m,3H), 2.18-1.81 (m, 2H), 1.60-1.34 (m, 2H), 1.20 (m, 3 H), 0.93 (d, J=6.8H); ¹³C NMR (CD₃OD) d165.8, 156.6, 146.0, 128.6, 124.0, 122.6, 116.8,115.9, 68.5, 67.4, 60.2, 59.54, 59.48, 58.8, 56.5, 45.0, 37.0, 36.9,31.9, 31.7, 30.99, 30.96, 27.6, 27.0, 26.7, 26.1, 15.9, 13.7; HPLC-MS(ammonium acetate) [M+H]⁺=372.21.

The product (18 mg, 48 μmol) was diluted in ether and oxalic acid (5.6mg, 62 μmol) dissolved in acetone was added. The resulting crystallinematerial was washed with ether to yield the corresponding oxalic salt(14 mg).

Separation of Diastereoisomers (AC00261434 & AC00261435)

The diastereomeric mixture of4-[3-(3-ethoxyimino-8-aza-bicyclo[3.2.1]oct-8-yl)-2(R)-methyl-propyl]-4H-benzo[1,4]oxazin-3-onewas separated with HPLC chiral phase chromatography. Retention times onan analytical column Chiralcel AD column ((250×4.6 mm, 10 μ) elutingwith hexane: EtOH (99: 1, with 0.3% diethylamine), 1 ml/min flow rate)are; the first isomer (AC00261434): 25.3 min, and the second isomer(AC00261435): 30.7 min.

4-[3-(3-Cyclopropylmethoxyimino-8-aza-bicyclo[3.2.1]oct-8-yl)-2(R)-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(diastereomeric mixture) (AC00261537)

A 7 ml vial was charged with4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (330 mg, 1.0mmol), crude O-cyclopropylmethyl-hydroxylamine chloride, K₂CO₃ (290 mg,2.1 mmol) and dry DMF (4 ml) and the reaction was shaken at 60° C. for 3days. The reaction was then poured into water and extracted with ether.The combined organic phase was washed brine, dried (Na₂SO₄), filtered,and concentrated under reduced pressure. The oily residue was purifiedby ion-exchange column chromatography to yield the diastereomericmixture of the title compound as an oil (80 mg, 0.20 mmol, 31% over twosteps). ¹H NMR (CDCl₃) d 7.20-7.15 (m, 1H), 7.02-6.95 (m, 3H), 4.65-4.51(m, 2H), 4.09-3.98 (m, 2H), 3.85-3.76 (m, 2H), 3.33-3.16 (m, 2H), 2.95(br t, J=16 Hz, 1H), 2.60-2.243 (m, 1H), 2.42-2.35 (m, 1H), 2.3-2.21 (m,1H), 2.20-2.04 (m, 2 H), 2.03-1.90 (m, 3H), 1.66-1.38 (m, 2H), 1.16-1.02(m, 1H), 0.90 (d, J=6.8 Hz, 3H), 0.56-0.44 (m, 2H), 0.32-0.18 (m, 2H);¹³C NMR (CDCl₃) d 161.9, 152.9, 142.8, 125.9, 120.8, 119.7, 119.6,114.3, 112.64, 112.63, 75.09, 75.07, 64.8, 57.6, 56.8, 56.6, 55.9, 54.1,54.0, 42.2, 34.7, 34.6, 29.6, 29.3, 28.34, 28.32, 25.3, 24.4, 24.3,23.5, 14.01, 13.99, 7.5, 0.1, 0.02, 0.00; HPLC-MS (ammonium acetate)[M+H⁺]=398.21.

(R,S)-4-[3-(4-Cyclopropylmethoxypiperidin-1-yl)-2-methoxypropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one(AC00262784)

A reaction vial was charged with crude(R,S)-7-Fluoro-4-(3-iodo-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one(0.113 g), cyclopropylmethoxypiperidine (145LH49) (0.047 g, 0.3 mmol),and K₂CO₃ (0.062 g, 0.45 mmol) in MeCN (2 mL) and stirred at 40° for 2days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic phases were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography followed by flash column chromatography(SiO₂; EtOAc) and prep RP-HPLC to give the title compound (0.024 g). ¹HNMR (CDCl₃) d 7.11-7.07 (m, 1H), 6.58-6.53 (m, 2H), 4.48-4.35 (m, 2H),3.97-3.93 (m, 1H), 3.83-3.77 (m, 1H), 3.48 (br s, 1H), 3.16-3.10 (m,6H), 2.65-2.63 (m, 2H), 2.36-2.23 (m, 2H), 2.03-2.00 (m, 2H), 1.77-1.67(m, 2H), 1.48-1.38 (m, 2H), 0.92-0.82 (m, 1H), 0.38-0.33 (m, 2H),0.04-0.00 (m, 2H); ¹³C NMR (CDCl₃) d 164.0, 158.8 (d, J=243.7 Hz), 146.3(d, J=11.5 Hz), 125.8 (d, J=3.5 Hz), 116.8 (d, J=9.6 Hz), 109.0 (d,J=22.7 Hz), 104.8 (d, J=25.8 Hz), 76.7, 72.6, 67.8, 59.4, 58.0, 52.4,52.1, 45.2, 31.5, 11.0, 3.0.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.029 g). HPLC-MS(ammonium acetate) [M+H]⁺=393.33.

1-[3-(3a-Cyclopropylmethoxy-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(AC00262572)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg,0.30 mmol), 3a-cyclopropylmethoxy-8-aza-bicyclo[3.2.1]octane (54 mg,0.30 mmol), NaI (75 mg, 0.50 mmol), and K₂CO₃ (69 mg, 0.50 mmol) in dryCH₃CN (2.5 ml). The reaction was shaken at 50° C. for 3 days and thereaction was poured into water and extracted with EtOAc. The organicphase was washed with brine, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The oily residue was purified by ion-exchangecolumn chromatography followed by flash column chromatography (SiO₂;EtOAc/MeOH 90:10) to yield the title compound as an oil (59 mg, 0.14mmol, 28%). ¹H NMR (CDCl₃) d 6.03 (dd, J=6.8, 12.4 Hz, 1H), 6.81-6.74(m, 2H), 3.78 (t, J=7.2 Hz, 2 H), 3.37 (t, J=4.8 Hz, 1H), 3.03 (d, J=6.4Hz, 2H), 3.01-2.96 (m, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.46-2.41 (m, 2H),2.22 (t, J=6.8 Hz, 2H), 1.93-1.15 (m, 10H), 0.89-0.77 (m, 1H), 0.40-0.27(m, 2H), 0.08-(−)0.04 (m, 2H); ¹³C NMR (CDCl₃) d 166.7, 146.4 (dd, J=13,243 Hz), 142.6 (dd, J=13 243 Hz), 133.7 (d, J=8 Hz), 119.6 (br), 113.5d, J=18 Hz), 102.5 (d, J=22 Hz), 69.9, 69.2, 55.9, 46.5, 38.3, 32.8,23.4, 23.3, 22.2, 8.1, 0.0; HPLC-MS (ammonium acetate) [M+H]⁺=405.30.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.049 g).

1-[3-(4-Cyclopropylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(AC00262272)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg,0.30 mmol), 4-cyclopropylmethoxypiperidine (145LH49) (42 mg, 0.27 mmol),NaI (75 mg, 0.50 mmol), and K₂CO₃ (69 mg, 0.50 mmol) in CH₃CN/DMF (1 ml,50:50). The reaction was shaken at 50° C. for 3 days and the reactionwas poured into water and extracted with EtOAc. The organic phase waswashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The oily residue was purified by ion-exchange columnchromatography followed by flash column chromatography (SiO₂; EtOAc) toyield the title compound as an oil (83 mg, 0.22 mmol, 81%). ¹H NMR(CDCl₃) d 6.90 (dd, J=6.8, 12.0 Hz, 1H), 6.82-6.75 (m, 1H), 3.73 (t,J=7.2 Hz, 2H), 3.22-3.13 (m, 1H), 3.11 (d, J=6.8 Hz, 2H), 2.69-2.54 (m,4H), 2.47-2.41 (m, 2H), 2.23-2.17 (m, 2H), 2.01-1.91 (m, 2H), 1.78-1.58(m, 4H), 1.52-1.40 (m, 2H), 0.94-0.82 (m, 1H), 0.44-0.28 (m, 2H),0.06-(−)0.03 (m, 2H); ¹³C NMR (CDCl₃) d 166.4, 146.1 (dd, J=13, 243 Hz),142.3 (dd, J=13, 243 Hz), 133.3 (dd, J=3, 8 Hz), 119.4 (dd, J=2, 5 Hz),113.3 (d, J=18 Hz), 102.0 (d, J=22 Hz), 71.5 (br), 69.5, 52.2, 48.3,38.0, 28.6, 28.2, 21.9, 21.7, 7.9, 0.0; HPLC-MS (ammonium acetate)[M+H]⁺=379.29.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.085 g).

1-[3-(4-Cyclobutylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(AC00262195) and carbonic acid cyclobutylmethyl ester1-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propyl]-piperidin-4-ylmethylester (AC00262296)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (130 mg,60%, 0.30 mmol), a mixture of 4-cyclobutylmethoxypiperidine and carbonicacid cyclobutylmethyl ester piperidine-4-ylester (42 mg), NaI (75 mg,0.50 mmol), and K₂CO₃ (69 mg, 0.50 mmol) in CH₃CN/DMF(1 ml, 50:50). Thereaction was shaken at 50° C. for 3 days and the reaction was pouredinto water and extracted with EtOAc. The organic phase was washed withbrine, dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The oily residue was purified by ion-exchange columnchromatography followed by flash column chromatography (SiO₂; EtOAc) toyield two products:1-[3-(4-Cyclobutylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-oneand carbonic (29 mg, 75 μmol) and Carbonic acid cyclobutylmethyl ester1-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propyl]-piperidin-4-ylmethylester (12.2 mg, 36 μmol).

1-[3-(4-Cyclobutylmethoxypiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-oneand carbonic: ¹H NMR (CDCl₃) d 7.08 (dd, J=7.2, 12.4 Hz, 1 H), 6.94 (m,1H), 3.90 (t, J=7.2 Hz, 2H), 3.40 (d, J=6.8 Hz, 2H), 3.32 (m, 1H), 2.82(t, J=6.8 Hz, 2H), 2.76-2.68 (m, 2H), 2.63-2.58 (m, 2H), 2.57-2.46 (m,1H), 2.34 (t, J=6.8 Hz, 2H), 2.16-2.00 (m, 4H), 1.94-1.56 (m, 11H); ¹³CNMR (CDCl₃) d 169.7, 149.4 (dd, J=13, 243 Hz), 145.6 (dd, 13, 243 Hz)136.6 (br), 122.7 (br), 116.6 (d, J=18 Hz), 105.3 (d, J=23 Hz), 75.0(br), 72.7, 55.5, 51.5, 41.3, 35.6, 31.8, 31.5, 25.325.2, 25.0, 18.8;HPLC-MS (ammonium acetate) [M+H]⁺=393.20.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added to the different solutions. The formed crystals werefiltered and washed with acetone to give the corresponding oxalic salt(0.028 g).

Carbonic acid cyclobutylmethyl ester1-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propyl]-piperidin-4-ylmethylester: ¹H NMR (CDCl₃) d 7.05 (dd, J=6.8, 12.4 Hz, 1H), 6.95 (m, 1H),4.64 (m, 1H), 4.10 (d, J=7.2 Hz, 2H), 3.9 (t, J=7.2 Hz, 2H), 2.82 (t,J=6.8 Hz, 2H), 2.77-2.58 (m, 5H), 2.36 (t, J=7.2 Hz, 2 H), 2.28-2.18 (m,2H), 2.12-2.02 (m, 2H), 2.01-1.73 (m, 11H); ¹³C NMR (CDCl₃) d 169.7,155.1, 159.4 (dd, J=13, 243 Hz), 145.6 (dd, J=13, 243 Hz), 136.6 (br),122.7 (br), 116.7 (d, J=18 Hz), 105.2 (d, J=22 Hz), 74.3 (br), 55.4,51.0, 41.2 (25.2, 25.0, 24.9, 18.6; HPLC-MS (ammonium acetate)[M+H]⁺=437.17.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added to the different solutions. The formed crystals werefiltered and washed with acetone to give the corresponding oxalic salt(0.012).

2,2-Dimethylpropionic acid1-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propyl]piperidin-4-yl-methylester (AC00261673)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg,0.20 mmol), 2,2-dimethylpropionic acid piperidin-4-ylmethyl ester (45mg, 0.21 mmol) (40 mg, 0.20 mmol), and Cs₂CO₃ (200 mg, 0.60 mmol) in dryDMF (1 ml). The reaction was shaken at 80° C. for 3 days and thereaction was poured into water and extracted with EtOAc. The combinedorganic phase was washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The oily residue was purified byion-exchange column chromatography to yield the title product as an oil(26 mg, 62 μmol, 31%). ¹H NMR (CDCl₃) d 7.07 (dd, J=1.8, 3.1 Hz, 1H),6.98-6.91 (m, 1H), 3.94-3.87 (m, 4H), 2.94-2.86 (m, 2H), 2.82 (br t,J=6.8 Hz, 2H), 2.02 (dd, J=5.2, 7.6 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H),1.94 (dt, J=2.0, 11.6 Hz, 2H), 1.74-1.58 (m, 3H), 1.42-1.28 (m, 2H),1.91 (s, 9H); ¹³C NMR (CDCl₃) d178.7, 169.7, 149.3 (dd, J=13, 230 Hz),145.6 (dd, J=243, 13 Hz), 136.7 (br), 122.7 (br), 116.6 (d, J=18 Hz),105.3 (d, J=22 Hz), 68.8, 55.8, 53.7, 42.3, 39.1, 35.7, 31.1, 29.1,25.2, 24.9; HPLC-MS (ammonium acetate) [M+H]⁺=423.20.

2,2-Dimethylpropionic acid2-{1-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1yl)-propyl]piperidin-4-yl}ethylester (AC00261939)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg,0.20 mmol), 2,2-dimethyl-propionic acid 2-piperidin-4-yl-ethyl ester,and Cs₂CO₃ (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction wasshaken at 80° C. for 3 days and the reaction was poured into water andextracted with EtOAc. The organic phase was washed with brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The oilyresidue was purified by ion-exchange column chromatography to yield thetitle product as an oil (21 mg, 48 μmol, 24%). ¹H NMR (CD₃OD) d7.23-7.12 (m, 2H), 4.11 (t, J=6.0 Hz, 2H), 3.96 (t, J=7.2 Hz, 2H),3.18-3.06 (m, 2H), 2.88 (br t, 6.8 Hz, 2H), 2.66-2.58 (m, 4H), 2.29 (dt,J=2.0, 12.0 Hz, 2H), 1.94-1.85 (m, 2H), 1.81 (br d, J=13.6 Hz, 2H),1.64-1.57 (m, 2H), 1.57-1.45 (m, 1H), 1.42-1.31 (m, 2H), 1.18 (s, 9H);¹³C NMR (CD₃OD) d 178.9, 171.1, 149.2 (dd, J=13, 241 Hz) 145.8 (dd,J=13, 230 Hz), 135.0 (br), 123.8 (dd, J=4, 6 Hz), 116.5 (d, J=19 Hz),105.1 (d, J=23 Hz), 62.2, 55.0 53.2, 40.2, 38.6, 34.7, 31.1, 30.8, 26.4,24.3, 23.5; HPLC-MS (ammonium acetate) [M+H]⁺=437.22.

1-{3-[3-(2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]oct-8-yl]-propyl}-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one(AC00262356)

A 4 ml vial was charged with1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (78 mg,0.30 mmol),3-(2-cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]octane (42 mg,0.2 mmol), NaI (75 mg, 0.50 mmol), and K₂CO₃ (69 mg, 0.50 mmol) inCH₃CN/DMF(1 ml, 50:50). The reaction was shaken at 50° C. for 3 days andthe reaction was poured into water and extracted with EtOAc. The organicphase was washed with brine, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The oily residue was purified by ion-exchangecolumn chromatography followed by flash column chromatography (SiO₂;EtOAc/MeOH, 90:10) to yield the title compound as an oil (46 mg, 0.11mmol, 53%). ¹H NMR (CDCl₃) d 7.14 (dd, J=6.8, 12.4 Hz, 1H), 6.95-6.88(m, 1H), 5.40 (t, J=6.6 Hz, 1H), 3.99-3.86 (m, 4H), 3.33-3.25 (m, 2H),3.21 (d, J=6.8 Hz, 2H), 2.8 (t, J=6.8 Hz, 2H), 2.62-2.53 (m, 3H), 2.48(t, J=6.8 Hz, 2H), 2.25 (br s, 1H), 1.95-1.74 (m, 5H), 1.58-1.36 (m,2H), 1.08-0.96 (m, 1H), 0.56-0.44 (m, 2H), 0.22-0.08 (m, 2H); ¹³C NMR(CDCl₃) d 166.5, 146.2 (dd, J=13, 243 Hz), 142.4 (dd, J=13, 243), 134.2,133.4 (br), 120.7 (br), 119.4 (br), 113.3 (d, J=18 Hz), 102.1 (br),71.8, 63.0, 56.7, 56.4, 45.3, 38.0, 37.7, 30.9, 28.6, 23.9, 23.6, 23.0,22.0, 7.7, 0.0; HPLC-MS (ammonium acetate) [M+H]⁺=398.21.

The product was dissolved in acetone and oxalic acid dissolved inacetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.046 g).

(R,S)-4-{3-[3a-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one

A reaction flask was charged with(R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (0.180 g,60% pure, 0.45 mmol), 3a-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane(0.078 g, 0.43 mmol), NaI (0.150 g, 1.0 mmol) and K₂CO₃ (0.138 g, 1.0mmol) in MeCN (1 mL) and stirred at 50° for 3 days. The reaction mixturewas quenched with water and the product extracted into EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The product was purified by cation exchange columnchromatography and flash column chromatography (SiO₂; EtOAc, EtOAc/MeOH10:1) to give the title compound (0.045 g). Major isomer: ¹H NMR (CDCl₃)d 7.32-7.26 (m, 1H), 7.02-6.95 (m, 3H), 4.66-4.52 (m, 2), 4.11-3.99 (m,2H), 3.48-3.38 (m, 4H), 3,16-3.02 (m, 2), 2.33-2.25 (m, 1H), 2.17-1.20(m, 13H), 1.19 (m, 3H), 0.88-0.86 (m, 3); ¹³C NMR (CDCl₃) d 164.7,145.5, 128.6, 123.5, 122.4, 116.9, 115.8, 69.7, 67.6, 66.1, 60.5, 58.7,57.9, 45.0, 38.0, 36.6, 36.3, 31.4, 27.8, 26.8, 24.9, 16.8, 15.2.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.042 g). HPLC-MS(ammonium acetate) [M+H]⁺=387.43.

(R)-4-{3-[3a-(2-Methoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00263025)

A reaction flask was charged with(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.199 g, 0.60mmol), 3a-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane (0.102 g, 0.60mmol), and K₂CO₃ (0.138 g, 1.00 mmol) in MeCN (2 mL) and stirred at 50°for 4 days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange COLUMN CHROMATOGRAPHY and flash COLUMN CHROMATOGRAPHY (SiO₂;EtOAc) to give the title compound (0.184 g, 83%). Major isomer: ¹H NMR(CDCl₃) d 7.31-7.28 (m, 1H); 7.02-6.93 (m, 3H); 4.70-4.52 (m, 2H);4.08-4.05 (m, 2H); 3.38 (t, J=6.6 Hz, 3H); 3.32 (s, 3H); 3.14-3.06 (m,2H); 2.31-2.26 (m, 1H); 2.18-1.54 (m, 13H); 1.32-1.20 (m, 2H); 0.87 (d,J=6.7, 3H); ¹³C (CDCl₃) d 165.1, 145.9, 129.1, 123.9, 122.8, 117.3,116.3, 72.3, 68.0, 61.0, 59.08, 58.98, 58.4, 45.5, 38.3, 37.0, 36.8,31.8, 28.3, 27.6, 25.3, 17.3; HPLC-MS (ammonium acetate) [M+H]⁺=373.18.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.178 g).

(R)-4-{3-[3a-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC0026320 1)

A reaction flask was charged with(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.06 g, 3.2mmol), 3a-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.589 g, 3.2 mmol),and K₂CO₃ (0.700 g, 5.1 mmol) in MeCN (4 mL) and stirred at 50° for 3days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography and flash column chromatography (SiO₂;EtOAc) to give the title compound (0.602 g, 49%). Major isomer: ¹H NMR(CDCl₃) d 7.30-7.26 (m, 1H), 7.02-6.96 (m, 3H), 4.66-4.53 (m, 2H),4.07-4.04 (m, 2H), 3.48-3.39 (m, 4H), 3.13-3.05 (m, 2H), 2.30-2.26 (m,1H), 2.16-2.03 (m, 3H), 1.95-1.80 (m, 4H), 1.74-1.68 (m, 2H), 1.63-1.56(m, 2H), 1.30-1.23 (m, 2H), 1.19 (t, J=45 Hz, 3H), 0.87 (d, J=6.7 Hz,3); ¹³C (CDCl₃) d 164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.8, 69.8,67.6, 66.1, 60.6, 58.7, 57.9, 45.1, 38.0, 36.6, 36.3, 31.4, 27.8, 26.8,24.9, 16.8, 15.2; HPLC-MS (ammonium acetate) [M+H]⁺=387.39.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt

(S)-4-{3-[3a-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00262993)

A reaction flask was charged with(R)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (1.06 g, 3.2mmol), 3a-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.589 g, 3.2 mmol),and K₂CO₃ (0.700 g, 5.1 mmol) in MeCN (4 mL) and stirred at 50° for 3days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography and flash column chromatography (SiO₂;EtOAc) to give the title compound (0.914 g, 74%). Major isomer: ¹H NMR(CDCl₃) d 7.29-7.26 (m 1H); 7.02-6.96 (m, 3H), 4.66-4.52 (m, 2H),4.12-4.01 (m, 2H), 3.48-3.38 (m, 4H), 3.13-3.04 (m, 2H), 2.30-2.26(m,1H), 2.16-2.03 (m, 3H), 1.96-1.79 (m, 4H), 1.73-1.68 (m, 2H),1.65-1.56 (m, 2H), 1.31-1.23 (m, 2H), 1.17 (t, J=4.3 Hz, 3); 0.86 (d,J=6.6 Hz, 3H); ¹³C NMR (CDCl₃) d 164.7, 145.5, 128.7, 123.5, 122.4,116.9, 115.8, 69.8, 67.6, 66.1, 60.6, 58.7, 57.9, 45.0, 38.0, 36.6,36.3, 31.4, 27.8, 26.8, 24.9, 16.8, 15.2; HPLC-MS (ammonium acetate)[M+H]⁺=387.41.

The product was dissolved in acetone and 1.1 equiv oxalic acid dissolvedin acetone was added. The formed crystals were filtered and washed withacetone to give the title compound as oxalic salt (0.142 g).

(S)-4-{3-[3a-(2-Methoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00263035)

A reaction flask was charged with(R)-4-(3-iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.265 g, 0.80mmol), 3a-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane (0.112 g, 0.66mmol), and K₂CO₃ (0.210 g, 1.5 mmol) in MeCN (2 mL) and stirred at 50°for 4 days. The reaction mixture was quenched with water and the productextracted into EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The product was purified by cationexchange column chromatography and flash column chromatography (SiO₂;EtOAc) to give the title compound (0.151 g, 62%). Major isomer: ¹H NMR(CDCl₃) d 7.33-7.28 (m, ¹H); 7.05-6.98 (m, 3H); 4.69-4.54 (m, 2H);4.10-4.06 (m, 2H; 3.39 (t, J=6.7 Hz, 2H); 3.34 (s, 3H); 2.33-2.29 (m,1H); 2.27-1.22 (m, 13H); 0.88 (d, J=6.6 Hz, 3H); ¹³C NMR (CDCl₃) d165.2, 145.9, 129.1, 123.9, 122.9, 117.3, 116.3, 72.4, 68.1, 61.1,59.10, 59.00, 58.4, 45.5, 38.3, 37.0, 36.8, 31.8, 28.2, 27.2, 25.3,17.3; HPLC-MS (ammonium acetate) [M+H]⁺=373.14.

(R)-4-{3-[3β-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00262998)

A reaction flask was charged with(S)-4-(3-iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.083 g, 0.25mmol), TFA salt of 3β-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane(162LH20) (0.059. g, 0.20 mmol), and K₂CO₃ (0.138 g, 1.0 mmol) in MeCN(2 mL) and stirred at 50° for 3 days. The reaction mixture was quenchedwith water and the product extracted into EtOAc. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The productwas purified by cation exchange column chromatography and flash columnchromatography (SiO₂; n-heptane/EtOAc 1:1, EtOAc) to give the titlecompound (0.039 g, 53%). Major isomer: ¹H NMR (CDCl₃) d 7.26-7.19 (m,1H), 6.96-6.90 (m, 3), 4.61-4.46 (m, 2H), 4.01-3.94 (m, 2H), 3.42-3.32(m, 4H), 3.14-3.00 (m, 2), 2.27-1.10 (m, 17H), 0.81 (d, J=6.6 Hz, 3H);¹³C NMR (CDCl₃) d 164.7, 145.4, 128.6, 123.5, 122.4, 116.9, 115.9, 68.3,67.6, 66.1, 61.5, 59.7, 58.0, 45.1, 38.5, 38.3, 36.9, 31.3, 27.1, 26.1,25.1, 16.9, 15.2; HPLC-MS (ammonium acetate) [M+H]⁺=387.11.

(S)-4-{3-[3β-(2-Ethoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[1.4]oxazin-3-one(AC00263034)

A reaction flask was charged with(R)-4-(3-iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (0.099 g, 0.30mmol), TFA salt of 3β-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.059.g, 0.20 mmol), and K₂CO₃ (0.138 g, 1.0 mmol) in MeCN (2 mL) and stirredat 50° for 4 days. The reaction mixture was quenched with water and theproduct extracted into EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The product was purified bycation exchange column chromatography and flash (SiO₂; EtOAc) to givethe title compound (0.040 g, 49%). Major isomer: ¹H NMR (CDCl₃) d7.43-7.24 (m, 1H), 7.06-6.72 (m, 3H), 4.70-4.55 (m, 2H), 4.14-4.02 (m,2H), 3.51-3.40 (m, 4H), 3.16-3.08 (m, 2H), 2.36-2.28 (m, 1H), 2.19-1.28(m, 13H), 1.21 (t, J=7.0 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H); HPLC-MS(ammonium acetate) [M+H]⁺=387.13.

EXAMPLE 3 Pharmacological Data

Receptor Selection and Amplification (R-SAT) assays were carried outusing the cloned M1-M5 receptors essentially as described in:Brauner-Osborne H, Brann M R. Pharmacology of muscarinic acetylcholinereceptor subtypes (m1-m5): high throughput assays in mammalian cells.Eur J Pharmacol Jan. 4, 1996;295(1):93-102, and Spalding T A, Trotter C,Skjaerbaek N, Messier T L, Currier E A, Burstein E S, Li D, Hacksell U,Brann M R. Discovery of an ectopic activation site on the M(1)muscarinic receptor. Mol Pharmacol. 2002 June;61(6):1297-302.

Compound m1 m2 m3 m4 m5 Number % Efficacy pEC₅₀ % Efficacy pEC₅₀ %Efficacy pEC₅₀ % Efficacy pEC₅₀ % Efficacy pEC₅₀ 55-LH-28-1 87 7.5 415.8 na 66 6.2 na (1549) 77-LH-1 (1606) na na na na na 55-LH-28-8 45 6.767 <5.5 na 64 <5.5 nt (1598) 55-LH-12-2 72 7.3 35 6.2 na 68 6.0 na55LH44-A 54 6.5 na na 28 <5.5 nt 55LH54 57 6.4 na na na na 73MF01 90 7.755 6.3 na 65 6.8 49 6.2 73MF02 90 7.6 50 6.0 na 75 6.6 30 6.377LH02-1917 55 6.7 na na 37 <5.5 na 64LHY89-5 45 5.6 na na na nt64LHY89-6 80 7.4 35 6.2 na 50 6.5 48 6.2 64LHY91-5 69 6.8 na na 51 5.738 6.2 64LHY91-6 86 7.2 31 6.9 na 52 6.6 na 77LH22-A 76 7.1 na na na 37<5.5 82LHY19 81 7.7 39 6.3 na 46 6.8 nt 77LH61-A 79 7.5 28 <5.5 na 335.8 51 <5.5 81MF24 96 7.8 70 7.0 na nt nt 81MF763 92 7.5 47 6.6 na 576.4 50 5.9 85LM47A 122 7.9 74 6.0 na 91 6.1 35 <5.5 85LM96-86R 106 7.697 6.2 30 5.9 94 5.8 90 5.6 85LM96-87R 101 7.7 116 5.9 36 6.0 140 6.1 626.0 107LH55 103 8.9 28 7.5 na 54 7.3 na 108LM39-36 106 8.8 37 8.1 na 717.7 na 107LH74-3D 97 8.0 na nt nt nt 112KK20-c5 117 8.3 na na nt nt107LH95-1 103 7.6 na nt nt nt

COMPOUND M1 M₁ M₂ M₂ M₃ M₃ ID Eff pEC₅₀ Eff pEC₅₀ Eff pEC₅₀ 00261478 1055.8 40 5.9 na na 00261435 121 8.4 128 7.1 82.8 6.2 00261434 110 6.2 505.7 na na 00262198 48 5.4 na na na na 00262197 122 6.8 28 5.6 na na00261537 126 6.9 58 6.1 na na 00262922 84 7.1 40 5.9 na na 00262909 1378.6 124 7.4 52 6.4 00262908 126 7.9 103 6.2 74 5.6 00262874 87 6.2 na nant nt 00262869 32 5.8 na na nt nt 00262867 104 7.1 32 5.8 na na 0026278494 7.1 71 5.7 na na 00262696 83 6.2 na na na na 00262635 96 7.2 53 6.1na na 00262573 120 8.4 72 7.3 na na 00262572 82 8.0 31 6.7 na na00262571 81 7.9 45 7.4 na na 00262569 97 8.2 42 7.3 na na 00262471 866.1 na na nt nt 00262469 98 7.2 73 6.3 na na 00262461 95 7.3 61 6.2 nana 00262357 79 7.9 na na na na 00262273 155 7.6 98 6.1 35 5.8 0026227294 7.3 57 6.0 na na 00262271 110 8.3 69 6.4 na na 00261939 na na na nana na 00261673 na na na na na na 00262356 46 7.5 na na na na 00263035 976.6 na na nt nt 00263034 68 6.8 na na nt nt 00263025 116 8.5 123 6.8 nana 00262998 102 8.1 56 6.4 nt nt 00262993 55 7.1 na na nt nt 00263201126 9.0 52 7.1 30 6.8

1. A compound of formula (I), and salts and isomers thereof

wherein: m is 0, 1 or 2; C₃-C₄ is CH₂—CR¹R⁹ or CH═CR¹ or C₄ is CR¹R⁹ andC₃ is absent; R¹ is selected from the group consisting of hydroxy,straight- or branched-chain C₁₋₆ alkylidene substituted with optionallysubstituted C₁₋₆ alkoxy, straight- or branched-chain C₁₋₆ alkoxysubstituted with optionally substituted C₃₋₈ cycloalkyl, ethoxyethyl,straight- or branched-chain C₁₋₆ heteroalkyl substituted with halogen,straight- or branched-chain optionally substituted C₁₋₆ haloalkyl,straight- or branched-chain optionally substituted C₁₋₆ alkyloxyimino,and straight- or branched-chain optionally substituted—OC(O)O(CH₂)_(s)CH₃; R⁹ is selected from the group consisting ofhydrogen, halogen, hydroxy, straight- or branched-chain optionallysubstituted C₁₋₆ alkyl, straight- or branched-chain optionallysubstituted C₂₋₆ alkenyl, straight- or branched-chain optionallysubstituted C₂₋₆ alkynyl, straight- or branched-chain optionallysubstituted C₁₋₆ alkylidene, straight- or branched-chain optionallysubstituted C₁₋₆ alkoxy, straight- or branched-chain optionallysubstituted C₁₋₆ heteroalkyl, straight- or branched-chain optionallysubstituted C₁₋₆ aminoalkyl, straight- or branched-chain optionallysubstituted C₁₋₆ haloalkyl, straight- or branched-chain optionallysubstituted C₁₋₆ alkoxycarbonyl, straight- or branched-chain optionallysubstituted C₁₋₆ hydroxyalkoxy, straight- or branched-chain optionallysubstituted C₁₋₆ hydroxyalkyl, straight- or branched-chain optionallysubstituted C₁₋₆ alkylthio, straight- or branched-chain optionallysubstituted —O—C₂₋₆ alkenyl, straight- or branched-chain optionallysubstituted —O—C₂₋₆ alkynyl, straight- or branched-chain optionallysubstituted C₃₋₆ alkenylalkoxy, straight- or branched-chain optionallysubstituted C₁₋₆ alkyloxyimino, straight- or branched-chain optionallysubstituted C₁₋₆ alkyloxyamino, optionally substituted —O—CH₂—C₅₋₆ aryl,—C(O)NR¹⁰R¹¹, —CR¹⁰R¹¹R¹², —OC(O)R¹⁰, straight- or branched-chainoptionally substituted —(O)(CH₂)_(s)NR¹¹R¹², straight- or branched-chainoptionally substituted —(CH₂)_(s)NR¹¹R¹², straight- or branched-chainoptionally substituted —OC(O)O(CH₂)_(s)CH₃, straight- or branched-chainoptionally substituted —S—C₁₋₆-alkyl, straight- or branched-chainoptionally substituted —S—C₂₋₆-alkenyl, and straight- or branched-chainoptionally substituted —S—C₂₋₆-alkynyl, each of which may be optionallysubstituted with one or more substituents R_(x); each R¹⁰ is separatelyselected from the group consisting of hydrogen, straight- orbranched-chain C₁₋₆ alkyl, straight- or branched-chain C₂₋₆ alkenyl,straight- or branched-chain C₂₋₆ alkynyl, straight- or branched-chainC₂₋₆ heteroalkyl, straight- or branched-chain C₂₋₆ aminoalkyl, straight-or branched-chain C₂₋₆ haloalkyl, straight- or branched-chain C₁₋₆alkoxycarbonyl, straight- or branched-chain C₂₋₆ hydroxyalkyl, C₃₋₈cycloalkyl, —C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo, C₅₋₆aryl, C₅₋₆ heteroaryl, C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl,—C(O)NR¹¹R¹², —CR¹¹R¹²R¹³, and straight- or branched-chain—(CH₂)_(s)NR¹¹R¹²; each s is separately selected to be an integer from 1to 8; each R¹¹ and each R¹² is separately selected from the groupconsisting of hydrogen, straight- or branched-chain C₁₋₆ alkyl, C₃₋₆cycloalkyl, and C₅₋₆ heteroaryl, or each R¹¹ and R¹² together form aC₃₋₈ cycloalkyl or C₃₋₈ heterocycloalkyl; R¹³ is selected from the groupconsisting of hydrogen, halogen, straight- or branched-chain C₁₋₆ alkyl,formyl, and C₃₋₆ cycloalkyl; each R_(x) is separately selected from thegroup consisting of hydrogen, halogen, hydroxy, straight- orbranched-chain optionally substituted C₁₋₆ alkyl, straight- orbranched-chain optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈ heterocyclyl,and straight- or branched-chain optionally substituted C₁₋₆ alkylidene;R² and R³ are separately selected from the group consisting of hydrogen,optionally substituted C₁₋₆ alkyl, optionally substituted O—C₁₋₆ alkyl,halogen, hydroxy or selected such that R² and R³ are covalently linkedtogether to form a ring system, wherein the ring system is formed byselecting R², R³, m, and C₃-C₄ such that

is selected from the group consisting of

wherein R⁸ is present 0, 1, or 2 times and is independently selectedfrom the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted O—C₁₋₆ alkyl, halogen, and hydroxy; each R⁴ andeach R⁵ are separately selected from the group consisting of hydrogen,halogen, hydroxy, optionally substituted C₁₋₆-alkyl, optionallysubstituted O—C₁₋₆ alkyl, optionally substituted aryl-C₁₋₆ alkyl, andoptionally substituted arylheteroalkyl; L¹ and L² are separatelybiradicals having the formula —C(R⁶)═C(R⁷); Y is selected from the groupconsisting of O, S, and H₂; and X is a biradical having the formulaC(R⁶)(R⁷)—O—, wherein R⁶ and R⁷ are separately selected from the groupconsisting of hydrogen, halogen, hydroxy, nitro, cyano, NR^(N)R^(N),N(R^(N))—C(O)—N(R^(N)), optionally substituted C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, optionally substituted O—C₁₋₆-alkyl, optionallysubstituted O-aryl, optionally substituted O—C₂₋₆-alkenyl, optionallysubstituted O—C₂₋₆-alkynyl, wherein R^(N) is selected from the groupconsisting of hydrogen, and optionally substituted C₁₋₆-alkyl.
 2. Thecompound of claim 1, wherein: R_(x) is selected from the groupconsisting of halogen, optionally substituted C₃₋₈ cycloalkyl,optionally substituted straight- or branched-chain C₁₋₆ alkyl, andoptionally substituted C₁₋₆ alkoxy.
 3. The compound of claim 2, wherein:R_(x) is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and halogen.
 4. The compound according to claim1, wherein R² and R³ are hydrogen or R², R³, C₃-C₄ and m are selectedsuch that

is selected from the group consisting of


5. The compound according to claim 1, wherein R² and R³ are separatelyselected from the group consisting of hydrogen, optionally substitutedC₁₋₆ alkyl, optionally substituted O—C₁₋₆ alkyl, halogen and hydroxy. 6.The compound according to claim 1, wherein m is
 1. 7. The compoundaccording to claim 1, wherein m is 0, C₃ is absent, and C₄ is CH suchthat


8. The compound according to claim 1 wherein Y is selected from thegroup consisting of O and H₂.
 9. The compound according to claim 1,wherein R¹ is selected from the group consisting of:


10. The compound according to claim 9 selected from the group consistingof:


11. The compound according to claim 1, wherein the compound is


12. A pharmaceutical composition comprising an effective amount of acompound according to claim 1 or a pharmaceutically acceptable salt, orester thereof.
 13. A method of treating a disease in a mammal, whereinmodulation of the activity of a cholinergic receptor is associated witha physiologically beneficial response in said disease of said mammal,said method comprising administering an effective amount of a compoundaccording to claim 1, and wherein said disease is selected from thegroup consisting of cognitive impairment, forgetfulness, confusion,memory loss, attentional deficits, deficits in visual perception,depression, pain, sleep disorders, psychosis, increased intraocularpressure, Alzheimer's disease, Parkinson's disease, schizophrenia,Huntington's chorea, Friederich's ataxia, Gilles de la Tourette'sSyndrome, Downs Syndrome, Pick disease, dementia, clinical depression,age-related cognitive decline, attention-deficit disorder, sudden infantdeath syndrome, and glaucoma.
 14. The method according to claim 13,wherein the cholinergic receptor is a muscarinic receptor.
 15. Themethod according to claim 13, wherein the cholinergic receptor isselected from the group consisting of a muscarinic M₁-receptor subtypeand a muscarinic M₄-receptor subtype.
 16. The method according to claim13, wherein the physiologically beneficial response is associated withthe selective modulation of the muscarinic M₁-receptor subtype inrelation to the muscarinic M₂- or M₃-receptor subtypes.
 17. The methodaccording to claim 13, wherein the compound is a muscarinic agonist. 18.A method of treating a disease or condition in a mammal, said disease orcondition selected from the group consisting of cognitive impairment,forgetfulness, confusion, memory loss, attentional deficits, deficits invisual perception, depression, pain, sleep disorders, psychosis,increased intraocular pressure, Alzheimer's disease, Parkinson'sdisease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gillesde la Tourette's Syndrome, Downs Syndrome, Pick disease, dementia,clinical depression, age-related cognitive decline, attention-deficitdisorder, sudden infant death syndrome, and glaucoma, comprisingcontacting a cholinergic receptor with an effective amount of at leastone compound according to claim
 1. 19. A method of treating oralleviating the symptoms associated with a disorder in a mammal,comprising the administration of an effective amount of at least onecompound according to claim 1, said disorder associated with amuscarinic receptor, wherein said disorder is selected from the groupconsisting of cognitive impairment, forgetfulness, confusion, memoryloss, attentional deficits, deficits in visual perception, depression,pain, sleep disorders, psychosis, increased intraocular pressure,Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington'schorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, DownsSyndrome, Pick disease, dementia, clinical depression, age-relatedcognitive decline, attention-deficit disorder, sudden infant deathsyndrome, and glaucoma.
 20. The method according to claim 13, whereinthe physiologically beneficial response is due to modulation in terms ofM₁ agonism; M₁ and M₄ agonism; both M₁ agonism and D₂ antagonism; or M₁and M₄ agonism and D₂ antagonism.
 21. The compound of claim 1, wherein:m is 1; C₃-C₄ is CH₂—CR¹R⁹; R¹ is straight- or branched-chain C₁₋₆alkoxy substituted with optionally substituted C₃₋₈ cycloalkyl; R⁹ ishydrogen; R² and R³ are each hydrogen; each R⁴ and each R⁵ are hydrogen;and at least one R⁶ or R⁷ is C₁₋₆-alkyl.